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Insights into the performance of Iceland´s ITQ system in he context of sustainable development
Get PDFThe Individual Transferable Quota (ITQ) approach to fisheries management has been promoted as a way to improve efficiency by reducing biological and economic overfishing. However, ITQ´s have also been challenged from environmental and social perspectives while observed efficiency gains have fallen well below estimated potential. This thesis examines these topics in the context of Iceland´s ITQ system in order to shed light on the potential contribution of ITQ´s to sustainable development. Iceland´s ITQ system is a useful case for studying the impact of ITQ´s since it is one of the world´s oldest and is widely regarded as a success, while the historic importance of fishing to Iceland means that the impact of introducing ITQ´s has been subject to intense national scrutiny.
Paper I applies established indicators of industry concentration and competitive rivalry to quota holdings at company and vessel level across species in order to quantify changes in industry structure following the introduction of ITQ´s. For several species, concentration has reached levels associated with market power and further consolidation is increasingly hampered by regulatory limits. The results suggest that a review of these limits may be overdue.
Paper II investigates the large apparent gap between reported and potential economic rent in Iceland´s harvesting sector by quantifying the contribution of transfers to processing, fishermen and the government. The results indicate that cumulative transfers to these groups between 2002-2014 exceeded reported rent. A speculative explanatory model is presented in which stakeholder representatives cooperate in order to obfuscate resource rent from harvesting and reduce pressure for reallocation to society at large.
Paper III examines the transitional gains trap, a phenomenon claimed to reduce the political scope for reallocation of quota rent due to resistance from harvesters who paid for the quota rather than being granted them as a result of grandfathering. A potential measure of the trap, based on harvesters’ cumulative investment in quota, is developed and applied to the Icelandic ITQ system. Illustrative results indicate that the proposed measure was generally below 60% by 2016 and that the extent of the trap may only be partial some 25 years after the current system was introduced, although outcomes are sensitive to assumptions due to the cumulative nature of the measure. Lastly, it is shown that the proposed measure can decline over time when accumulated profits are set off against cumulative investment costs.
Paper IV analyses historic fuel use patterns by Icelandic harvesters for key segments and species and examines potential drivers. The results indicate that fuel intensity in the demersal sector has declined in recent years to levels which are low relative to other countries and that higher fish stocks have been an important contributory factor. A novel policy instrument to reduce industry greenhouse gas emissions is presented whereby ITQ´s are extended to cover emissions as well catch, with each harvester receiving individual transferable emissions quota in proportion to their catch share and Total Allowable Emissions set by the authorities.
Paper V explores patterns in usage of catch-quota balancing mechanisms in Iceland´s mixed demersal fishery. Panel data analysis indicates systematic behaviour consistent with arbitrage incentives, suggesting a high risk of consistently exceeding TAC limits. Despite this, overfishing has been relatively modest and this is attributed to limits which have been tightened and are particularly stringent for the main target species, cod.
This thesis explores the potential of the ITQ approach to contribute to sustainable development of fisheries along the three established dimensions (economy, society and environment). Results for the Icelandic ITQ system indicate a qualified success in meeting some of the key challenges. The system also exhibited flexibility in responding to emerging issues. Two avenues for further research are highlighted; pathways to carbon-neutral fishing and implications of different allocation methods. Research into the latter topic seems particularly warranted; fisheries economics has been relatively silent on the subject but frameworks can be found in the broader literature that may inform the sustainable development agenda to the extent that it involves creating limited valuable rights to use natural resources which must somehow be allocated.Financial support received from the GreenMAR project, funded by NordForsk (project number 61582)
Out-of-equilibrium hydrodynamics with and without boost symmetry
Get PDFIn this thesis, we explore the role of symmetries in hydrodynamics by studying certain
properties of relativistic and non-relativistic fluids. In the first part of the thesis, we
examine the theory of relativistic magnetohydrodynamics (Maxwell electromagnetism
coupled to hydrodynamics) and its low temperature incarnation, force-free electrodynamics, reformulated in the language of higher-form symmetries and discuss the
advantages of such a scheme. Using this framework, we analyse the regime of validity
of force-free electrodynamics by evaluating the lifetime of the non-conserved electric
field operator via a holographic model sharing the same global symmetries as that of a
plasma. We are able to explicitly calculate the lifetime of the electric field, both parallel
and perpendicular to the magnetic field, and find that there are indeed no long-lived
modes that interfere with a hydrodynamic description of force-free electrodynamics. In
the second part of the thesis, we study the thermodynamic properties of non-relativistic
Lifshitz fluids with an arbitrary dynamic exponent z (encoding the anisotropy in the
scaling of time and space coordinates). We study energy transport in such fluids far from
equilibrium after performing a local quench between two semi-infinite fluid reservoirs.
We find that the late time energy flow is universal and accommodated via a steady
state occupying an expanding central region between outgoing shock and rarefaction
waves (a non-equilibrium steady state), as seen previously for relativistic scale invariant
fluids. Armed with an equation of state for a perfect Lifshitz fluid with an arbitrary z
and moving with a velocity v, we proceed to study its holographic dual using the well established Einstein-Maxwell-Dilaton model. We find that the fluid velocity appears
as the chemical potential, conjugate to the dual momentum density and the solutions
represent a physically distinct class of black branes possessing a linear momentum,
different from boosting a static brane
Mucoadhesive drug delivery systems for the treatment of oral mucosal conditions
No full textThe oral mucosa is a convenient location where drug delivery systems could be employed to treat both local conditions as well as systemic delivery. It offers 4-4000 times more permeability relative to skin which makes it an ideal platform for delivering higher molecular weight compounds both for local as well as systemic delivery. The oral mucosa can be affected by some conditions that are local e.g., ulcerative conditions like aphthous ulcers, immunologically mediated conditions, hyperkeratosis and infections (bacterial, candida and virus (cold sores)). Some of these conditions require long-term clinical follow up which eventually could lead to drug resistance. There is a growing need to develop new treatments that are effective in reducing the inflammation and effectively treating the infections. Previous clinical trials and in vitro microbial tests proved that doxycycline is a promising alternative in downgrading the inflammation pathway and could be potentially useful in treatment of many oral conditions. Monocaprin is a lipid that is effective against various bacteria, yeast and viruses. It effectively healed cold sores in combination with doxycycline and treatment outcome was promising compared to the existing treatments. But the drawback was the stability of the compounds; doxycycline undergoes oxidation and epimerization while monocaprin undergoes hydrolysis and is also susceptible for acyl-migration in solutions and both the compounds need to be stabilized in formulations especially sensitive to aqueos formulations. So, the main aim of this project was focused on enhancing the stability of active components doxycycline and monocaprin and also stabilizing them in combination in a hydrogel formulation. The study also involved development of suitable HPLC/UPLC method for accurate chemical quantification of the active component. Further the physicochemical evaluation of the formulations was analyzed to optimize the formulations for the oral mucosal delivery. The formulations were also analyzed for mucoadhesion capacity and texture profile analysis to enhance the drug retention at application site and also to enhance the patient compliance. The doxycycline was successfully stabilized in aqueous formulation for a tested period of up to 5 years. A hydrogel containing combination of doxycycline and monocaprin was developed and both the active components were stabilized for a period up to 1 year at 4°C. The microparticles were further developed to enhance the doxycycline stability even at 25°C and films loaded with microparticles effectively stabilized doxycycline even at room temperature.
Various buccal films with different polymeric blends and plasticizers were evaluated for their suitability for doxycycline stability and their effect on films, mechanical properties, swelling index, pH, mucoadhesive potential and in vitro release with varying release time profile ranging from immediate-intermediate-sustained films were developed and evaluated. Suitable polymers and plasticizers for doxycycline stability are reported. Selection of polymers based on film properties that can be tailored are discussed in this work.
Overall, doxycycline formulation that is stable for 5 years was developed. A stable hydrogel containing combination of doxycycline and monocaprin was developed. An accurate HPLC method for monocaprin quantification was developed. Doxycycline was further stabilized in microparticles loaded buccal films even at room temperature. Effect of microparticles and their incorporation on doxycycline stability as well as film properties were evaluated. Suitable polymers and plasticizers for doxycycline, for buccal film development were studied and reported. This project successfully stabilized doxycycline in formulations, also in combination with monocaprin, that could deliver it for MMP inhibition for oral mucosa, were developed that could be commercially available
Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations
Get PDFPost-printCyclic guanosine monophosphorothioate analogue 1a is currently showing potential as a drug for the treatment of inherited retinal neurodegenerations. To support ongoing preclinical and clinical work, we have developed a diastereoselective synthesis via cyclization and sulfurization of the nucleoside 5′-H-phosphonate monoester, which affords the desired RP-3′,5′-cyclic phosphorothioate in 9:1 ratio to the undesired SP-diastereomer. This route was made viable as a result of the silyl protection sequence used, which achieved >80% selectivity for 2′,5′-hydroxyls over 3′,5′-hydroxyls. Finally, the chromatography-free process allowed for a scale-up, as intermediates and the final product were isolated by crystallization to give 125 g of 1a (13.8% total yield) with over 99.9% HPLC purity.The authors would like to thank Professor Thorsteinn Loftsson at the University of Iceland for his continued support and guidance, particularly to O.P. as academic supervisor, and Professor Jacek Stawiński at Stockholm University for fruitful discussions. We also thank Dr. Frank Schwede at BIOLOG Life Science Institute (Bremen, Germany) for discussions about synthetic strategy as well as providing material for structural comparisons to our product. This work was supported by the European Commission (H2020-MSCA-765441; HEALTH-F2-2012-304963)Peer Reviewe
Attractive and repulsive serial biases in visual cognition
Get PDFOur eyes are the primary gates to the visible world around us. Yet, whatever we perceive involves a translation of the patterns of the photons hitting our retinas into mental representations. It could be argued that visual perception is merely an interpretation of the physical world, which raises the question of how reliable this translator is. Fischer and Whitney (2014) found that the perception of an oriented Gabor patch was influenced by the orientation of previously presented Gabor patches, a phenomenon that they called serial dependence. They argued that serial dependence reflects the visual system's assumptions about continuity: The visual world around us is generally constant from moment to moment and does not suddenly change despite large changes in viewpoint, occlusion or lighting conditions. Our perceptual systems employ this predictability to overcome potential perceptual noise and maintain perceptual stability. Subsequent research has revealed that the perception of a variety of other features, including shape, motion coherence, numerosity, facial identity, and even stimulus ensembles, is systematically biased toward recent information. Almost all of the studies mentioned above involved paradigms where the stimuli causing the serial dependence (the inducers) were attended, and therefore do not address whether items that we ignore can cause serial dependence biases. In the papers in this thesis, we studied the role of the to-be-ignored items in forming biases in our perceptual decisions. In Paper I here, we used a visual search for an oddly oriented line among distractors to demonstrate that the to-be-ignored items can form serial dependence in perceptual decisions in addition to the attended inducer. Notably, the repulsive bias occurs even when the distractors and targets are remarkably dissimilar, which distinguishes this from the well-known tilt illusion and tilt adaptation. Furthermore, our results demonstrate that explicit reports of stimulus features are not required for serial dependence. The findings in Paper I suggest that perception accounts for both attended and ignored stimuli in preserving the visual world's continuity to a greater extent than previously thought. In Paper II we demonstrated that visual search can result in serial-dependence biases in the perceived orientation of a stimulus that is unrelated to the search task. Our findings also revealed that both attention and similarity between the search stimuli (distractors and targets) and the test item play a significant role in forming serial dependence in perceptual decisions. Finally, our findings in Paper III demonstrated that similar biases to those reported in Papers I and II can occur from a single inducer line upon a set of test lines as previously observed from a set of lines upon a single test line. Secondly Paper III shows that when the inducer is similar to the test, it produces an attractive bias, but it creates a repulsive bias when these items are dissimilar. This means that the inducer creates opposing biases based on the similarity of the perceptual history content to the current stimulus. These attractive and repulsive biases can occur simultaneously when more than one test item is present. Overall, our results show that attention and proximity in feature space play a crucial role in shaping serial dependence biases. We showed that biases introduced by attended versus ignored visual search items (targets and distractors) influenced the general perceptual decisions, and furthermore, we showed that even attended items can produce repulsive biases in perceptual decisions.Research Fund of the University of Iceland and the Icelandic Research fund (#173947-052
Photoluminescence study of Si<sub>1-x</sub>Ge<sub>x</sub> nanoparticles in various oxide matrices
Get PDFWe investigate the photoluminescence properties of structures comprising of Si1-xGex nanoparticles (NPs) within SiO2, GeO2, TiO2 and Ta2O5 oxide matrices. Of the investigated structures, it was observed that the structures with GeO2 and TiO2 matrices provide increased spectral response (at ~907 and 844 nm respectively) and increased PL intensity. The improved PL characteristic have been attributed to increased diffusion barrier against oxygen which otherwise would result in formation of unwanted oxide at the film-oxide interface, thereby deteriorating the optical properties.This work is partially funded by the Icelandic Research Fund Grants nos. 218029 and 196141.Pre-print (óritrýnt handrit
The Arctic Council An Agent of Change?
Get PDFThe geo-political importance of the Arctic is growing while at the same time
the onset of climate change has resulted in increasing environmental and
social pressures both on Arctic states and the governance architecture through
which Arctic issues are addressed. The Arctic Council is the primary
intergovernmental forum promoting cooperation, coordination and interaction
among Arctic States, Indigenous communities and peoples. This thesis looks
at how this body is evolving in response to these pressures. It explores the
drivers and barriers to its institutional effectiveness; and through the lens of
biodiversity considers how these may hinder or be conducive to its ability to
have an impact upon the issues it was formed to address i.e. environmental
protection and sustainable development. It does so through considering
Actions needed to ensure the sustainable conservation and management of the
Arctic’s biodiversity; identifying barriers to the effectiveness of the Council
in achieving its goals; and identifying mechanisms through which it seeks to
achieve its objectives
Extreme macrosomia – birth outcome for mother and infant, and metabolomic profile
Get PDFMarkmið: Að kanna áhættuþætti fyrir fæðingu mikilla þungbura (fæðingarþyngd ≥5000 g) og hugsanlegar afleiðingar þess fyrir móður og barn (grein 1). Að meta efnaskipti mikilla þungbura með því að skoða mynstur þeirra amínósýra og acylkarnitína sem mæld eru í nýburaskimun og bera saman við börn með eðlilega fæðingarþyngd og börn með lága fæðingarþyngd (<2500 g) (grein II). Jafnframt að meta hvaða áhrif fæðingarmáti hefur á efnaskipti barns við fæðingu með því að mæla magn ofangreindra þátta í naflastrengsblóði og við nýburaskimun þegar barnið er 2-3 daga gamalt (grein III).
Aðferðir: Fyrsti hluti verkefnisins var ferilrannsókn með öllum fæðingum mikilla þungbura sem fæddust á árunum 1996-2005. Fyrir hvern þungbura voru valin til samanburðar tvö fullburða börn sem höfðu eðlilega fæðingarþyngd (10.-90.‰ í íslensku þýði). Annar hlutinn var gagnagrunnsrannsókn byggð á niðurstöðum úr íslensku nýburaskimuninni með fullbura einburum fæddum á Íslandi á árunum 2009-2012. Þrír hópar með mismunandi fæðingarþyngd voru bornir saman: lág fæðingarþyngd (<2500 g), eðlileg fæðingarþyngd miðað við meðgöngulengd (10.-90.‰) og miklir þungburar (≥5000 g). Þriðji hluti verkefnisins var framskyggn rannsókn á börnum fæddum með eðlilegri fæðingu eða valkeisaraskurði og mæðrum þeirra frá nóvember 2013 til apríl 2014. Blóð frá móður fyrir fæðingu, naflastrengsblóð nýbura við fæðingu og niðurstöður nýburaskimunar voru notuð til að bera saman amínósýrur og acýlkarnitín milli fæðingarmáta.
Niðurstöður: 343 miklir þungburar fæddust á árunum 1996-2005 eða 0,9% allra einbura (grein I). Mæður þeirra voru líklegri til að vera með hærri líkamsþyngdarstuðul og þyndaraukning þeirra á meðgöngu var marktækt hærri en mæðra barna með eðlilega fæðingarþyngd. Einnig var framköllun fæðingar ólíklegri til að takast hjá þeim og bráðakeisaraskurðir voru líklegri, en ekki valkeisaraskurðir. Miklir þungburar voru líklegri til að lenda í axlarklemmu í fæðingu og fá fæðingaráverka, en ekki að verða fyrir fósturköfnun. Minni háttar fæðingargallar og efnaskiptatruflanir voru algengari hjá miklum þungburum.
Í öðrum hluta verkefnisins (grein II), höfðu bæði nýburar með lága fæðingarþyngd og miklir þungburar hærri gildi af glútamínsýru en börn með eðlilega fæðingarþyngd miðað við meðgöngulengd. Þá var amínósýran þreónín hærri hjá börnum með lága fæðingarþyngd. Frítt karnitín og sumar af meðal- og langra-keðju acýlkarnitínum voru hærri hjá börnum með lága fæðingarþyngd. Hýdroxýbútýrýlkarnitín var lægra hjá börnum með lága fæðingarþyngd en hærra hjá miklum þungburum. Acetýlkarnitín var hærra hjá börnum með lága fæðingarþyngd og miklum þungburum.
Í samanburði við nýbura sem fæddir voru með valkeisaraskurði (grein III) voru nýburar fæddir á eðlilegan máta með hærri meðaltalsmun fyrir alanín, lysín, fenýlalanín, prólín, valín, samanlögð acýlkarnitín, própíónýlkarnitín, súkkinýlkarnitín, tetradekanóýlkarnitín, hexadekanóýlkarnitín, oktadekanóýlkarnitín og óleýlkarnitín við fæðingu. Enginn marktækur munur var á amínósýrum í blóðsýni móður og barns við nýburaskimun eftir leiðréttingu fyrir fjölda tölfræðilegra prófanna. Amínósýrur og minni stuttkeðju acýlkarnitín voru, óháð fæðingarmáta, hærri í naflastrengsblóði nýbura en blóði móður, að frátöldum arginínósúkkiniksýru, asparssýru og cítrúllini. Amínósýrur og acýlkarnitín voru hærri við nýburaskimun en í naflastrengssýnum í báðum fæðingarmátahópum, að frátöldum alaníni, arginíni, fenýlalaníni, þreóníni, valíni, fríu karnitíni og línóleóýlkarnitíni.
Ályktanir: Hár líkamsþyngdarstuðull og of mikil þyngdaraukning móður á meðgöngu auka áhættu á fæðingu mikilla þungbura. Í slíkum tilfellum er aukin hætta á fylgikvillum í fæðingu, bæði hjá móður og barni. Það virðist munur á efnaskiptum mikilla þungbura og barna með eðlilega fæðingarþyngd, sem kemur fram sem munur á mynstri þeirra amínósýra og acýlkarnitína sem mæld eru við nýburaskimun. Sá munur er ólíkur því mynstri sem kemur fram við samanburð fullburða barna með lága fæðingarþyngd miðað við eðlilega. Fæðingarmáti virðist tengjast mynstri þessara efna í blóði barna við fæðingu, þar sem börn sem fæðast með eðlilegri fæðingu hafa hærra gildi margra amínósýra og acýlkarnitína en börn fædd með valkeisaraskurði. Í nýburaskimuninni er þessi munur lítill sem enginn, sem bendir til þess að fæðingarmáti hafi ekki langvarandi áhrif.Háskólasjóður Eimskipafélags Íslands/Eimskip University Fund.
Nýsköpunarsjóður Námsmanna/Student Innovation Fund.
Aðstoðakennarasjóður Háskóla Íslands/Assistant Teacher fund in University of Iceland.
Vísindasjóður Landspítalans Háskólasjúkrahús/Science fund of Landspitali University Hospital.
Rannsóknarsjóður Kvennadeildar Landspítalans Háskólasjúkrahúss/Research Fund at the Women´s Clinic at Landspitali University Hostpital.
Rannsóknarsjóður Erfða- og sameindafræðisviðs Landspítalans Háskólasjúkrahúss/Research Fund of the Department of Genetics and Molecular Medicine, Landspitali University Hospital
Strained interface layer contributions to the structural and electronic properties of epitaxial V2O3 films
Get PDFWe report on the transport properties of epitaxial vanadium sesquioxide (V2O3) thin films with thicknesses in the range of 1 to 120 nm. Films with thickness down to nanometer values reveal clear resistivity curves with temperature illustrating that even at these thicknesses the films are above the percolation threshold and continuous over large distances. The results reveal that with reducing thickness the resistivity of the films increases sharply for thicknesses below 4 nm and the metal-insulator transition (MIT) is quenched. We attribute this increase to a strained interface layer of thickness ∼ 4 nm with in-plane lattice parameters corresponding to the Al2O3 substrate. The interface layer displays a suppressed MIT shifted to higher temperatures and has a room temperature resistivity 6 orders of magnitude higher than the thicker V2O3 films.This work was supported by the University of Iceland
Research Fund for Doctoral Students, the University of Iceland
Research Fund, the Icelandic Student Innovation Fund, and the
Icelandic Research Fund (Grant Nos. 207111 and 174271)
Survival and complications in patients with chronic lymphocytic leukemia in the pre-ibrutinib era
Get PDFInngangur: Langvinnt eitilfrumuhvítblæði (CLL) er sjúkdómur sem leggst helst á eldra fólk, meðalaldur þeirra sem greinast er um 72 ár. Langt fram eftir 20. öldinni var helsta meðferðin við sjúkdómnum chlorambucil, en í kringum aldamót breyttist meðferðin með tilkomu fludarabin. Seinna meir bættust rítúxímab og cýklófosfamíð við þá meðferð. CLL svaraði betur þessum lyfjum en engu að síður gekk illa að sýna fram á aukna lifun í lyfjarannsóknum. Einnig var gagnrýnt að meðalaldur sjúklinga í lyfjarannsóknunum var talsvert lægri en meðalaldur sjúklinga með CLL almennt. Fáar rannsóknir hafa metið hvernig fylgikvillar, lifun og dánarorsakir í CLL hafa breyst síðan um aldamót og þær hafa flestar verið smáar í sniðum. Við rannsökuðum þessar mikilvægu breytingar í lýðgrundaðri rannsókn til að meta þær meðferðarbreytingar sem áttu sér stað um síðustu aldamót.
Aðferðir: Þýðið var samansett úr sjúklingum sem voru skráðir með CLL samkvæmt sænsku krabbameinsskránni árin 1982-2013. Fyrir hvern CLL sjúkling var af handahófi valinn samanburðareinstaklingur af sama kyni og svipuðum aldri og búsetu. Upplýsingar um dánardag og dánarorsök var fengin frá sænsku dánarmeinaskránni. Upplýsingar um fyrri sjúkdóma, alvarlegar bakteríusýkingar og tækifærissýkingar fengust úr sænsku sjúklingaskránni. Eftirfylgd náði til 1. janúar 2014. Umframdánartíðnihlutfall (EMRR) og hlutfallsleg lifun (RS) voru reiknuð í líkönum sem leyfðu breytilega hlutfallsáhættu með 95% öryggisbilum (95% CI). Byrði fylgisjúkdóma var metin með Charlson fylgisjúkdómaskori (CCI). Líkan til að meta áhættu á bakteríusýkingum reiknaði áhættuhlutfall (HR) og leyfði endurtekna atburði. Áhætta á tækifærissýkingum var metin með nýgengishlutfalli (IRR) og horfur eftir sýkingu metnar með tilfella-dánarhlutfalli (CFR).
Niðurstöður: Þýðið samanstóð af 13,009 CLL sjúklingum. Samanborið við 1982-1992 var EMRR 0.72 (95% CI 0.66-0.77) árabilið 1993-2002 og 0.53 (0.48-0.58) árabilið 2003-2013. Lifun jókst jafnt og þétt yfir rannsóknartímabilið að yngsta aldurshópnum undanskildum. Hjá yngstu karlkyns CLL sjúklingunum minnkaði lifun lítillega til aldamóta en jókst eftir það (5 ára RS 0.87, 0.84 og 0.89 fyrir sjúklinga greinda 1982, 1992 og 2002, í sömu röð). CLL var aðaldánaorsök í 41-44% af þeim sem létust og var óbeint tengt allt að 70% af andlátum. Áhættan af því að deyja úr CLL minnkaði yfir rannsóknartímann (HR 0.78, 95% CI 0.75-0.81 fyrir hver 10 ár). Áhættan af
iii
því að deyja úr öðrum blóðsjúkdómum og sýkingum minnkaði einnig (HR 0.60, 95% CI 0.55-0.65 og HR 0.62, 95% CI 0.52-0.73 í sömu röð). Aukin byrði fylgisjúkdóma var tengd verri horfum, hvort sem dánarsökin var tengd CLL (HR 1.35, 95% CI 1.25-1.45 og HR 1.47, 1.37-1.57 fyrir 1 og 2+ CCI stig, í sömu röð) eða ótengd CLL (HR 1.45, 1.30-1.63 og HR 2.09, 1.90-2.30 fyrir 1 og 2+ CCI stig, í sömu röð).
Nýgengi (IR) innlagna vegna bakteríusýkinga var 15 á 100 sjúklingaár. Algengustu sýkingarnar voru lungnabólgur (IR 10.5), blóðsýking (IR 3.4), og húðsýkingar (IR 1.0). Þegar nýgengið var borið saman við viðmið, var áhættan mest fyrir blóðsýkingar (HR 6.91, 95% CI 6.46-7.39) og lungnabólgur (HR 5.91, 5.64-6.18). Áhættan af því að leggjast inn vegna bakteríusýkinga minnkaði á rannsóknartímanum (HR 0.87, 0.81-0.94 árin 1992-2002 og HR 0.76, 0.70-0.82 árin 2003- 2013, samanborið við 1982- 1992). Alls voru 829 innlagnir vegna tækifærissýkinga í 8,989 sjúklingum sem greindust með CLL árin 1994-2013. Algengasta sýkingin var lungnabólga vegna Pneumocystis jirovecii (IR 4.03 á 1,000 sjúklingaár) og áhættan var einnig mest samanborið við viðmið (IRR 114, 95% CI 58.7-252). Alvarlegar herpes zoster sýkingar voru næst algengasta sýkingin (IR 2.94). Næst komu sveppasýkingar vegna Candida (IR 1.66) og Aspergillus (IR 1.20) og höfðu þær sýkingar mjög slæmar horfur (CFR 33% og 42%, í sömu röð).
Ályktanir: Í stórri lýðgrundaðri rannsókn höfum við sýnt að lifun CLL sjúklinga hefur aukist undanfarna áratugi. Þegar dánarorsakir voru skoðaðar kom í ljós að þetta var að stórum hluta vegna bættrar lifunar m.t.t. CLL. Þessar niðurstöður styrkja fyrri niðurstöður um gagnsemi þeirrar CLL lyfjameðferðar sem var tekin upp um aldamót. Fylgikvillar jukust ekki á rannsóknartímanum, þvert á móti var lægri innlagnatíðni vegna alvarlegra bakteríusýkinga og á því að deyja úr sýkingum. Þessar niðurstöður eru mikilvægar því meðferðarárangur í lyfjatilraunum þarf að staðfesta í lýðgrunduðum rannsóknum á sjúklingum sem njóta almennrar þjónustu.Introduction: Chronic lymphocytic leukemia (CLL) is a disease of the elderly
and the median age of newly diagnosed patients is 72 years. CLL was
traditionally treated with chlorambucil, but it was replaced at the turn of the
century with fludarabine based chemo- and chemo-immunotherapy. These
therapies offered better response rates, however, most clinical trials failed to
show improved overall survival and elderly patients were underrepresented in
those trials. Infections cause a great burden for CLL patients and the
increased risk is both due to the disease itself and the treatment. Few studies
have estimated temporal changes in survival, causes of death and
complications of CLL and the literature is largely based on clinical trials and
single-center studies. To evaluate the effect of the treatment changes that
occurred at the turn of the century, we performed a nationwide study on
survival, causes of death and infections in CLL patients.
Methods: Information on CLL patients diagnosed 1982-2013 was
obtained from the Swedish Cancer Registry. For each CLL patient, four
controls matched for age, sex and place of residence were randomly
allocated. Information on date and cause of death was obtained from the
Swedish Cause of Death Registry. The Swedish Patient Register was used to
obtain information on serious inpatient bacterial infections, opportunistic
infections and on previous diagnoses for calculation of Charlson comorbidity
index (CCI). End of follow-up was January 1st 2014. In the survival and cause
of death analysis, flexible parametric models were used to assess excess
mortality rate ratios (EMRR), relative survival (RS) and hazard ratios (HR)
with 95% confidence intervals (95% CI). The risk of serious bacterial
infections was estimated in a recurrent event analysis. The risk of
opportunistic infections in CLL patients compared to matched controls was
estimated with an incidence rate ratio (IRR) and the impact was estimated
with a 60-days case fatality ratio (CFR).
Results: In the Swedish CLL cohort; 13,009 patients; survival increased
over time. Compared to the calendar period 1982-1992, the EMRR adjusted
for age and sex was 0.72 (95% CI 0.66-0.77) for 1993-2002 and 0.53 (95%
CI 0.48-0.58) for 2003-2013. The improvement was continuous over the
study period for all age groups except for the youngest CLL population. In
young male patients, survival trends were relatively static until 2000, after which there was a continuous improvement in survival. The 5-year RS in
males aged 50 years and younger was 0.87 (95% CI 0.78-0.92), 0.84 (95%
CI 0.78-0.89), and 0.89 (95% CI 0.84-0.93) for 1982, 1992, and 2002,
respectively. In general, CLL was the primary cause of death in 41-44% and
CLL was related to nearly 70% of the mortality. Over time, CLL decreased as
a cause of death (HR 0.78, 95% CI 0.75-0.81 for 10-year increase in
calendar year). Furthermore, other hematological diseases (HR 0.60, 95% CI
0.55-0.65) and infections (HR 0.62, 95% CI 0.52- 0.73) decreased as a cause
of death. Higher CCI was associated with increased risk of CLL-related
mortality (HR 1.35, 95% CI 1.25-1.45 and HR 1.47, 1.37-1.57 for 1 and 2+
CCI points, respectively) and increased risk of CLL unrelated mortality (HR
1.45, 1.30-1.63 and HR 2.09, 1.90-2.30 for 1 and 2+ CCI points,
respectively).
The incidence rate (IR) of serious bacterial infections in the CLL cohort
was 15 admissions per 100 patient years. The most common infections were
pneumonia (IR 10.5), septicemia (IR 3.4) and skin infections (IR 1.0). The risk
compared to matched controls was highest for septicemia (HR 6.91, 95% CI
6.46-7.39) and pneumonia (HR 5.91, 5.64-6.18). The risk of infections
decreased over time (HR 0.87, 0.81-0.94 in 1992-2002 and HR 0.76, 0.70-
0.82 in 2003- 2013, compared to 1982-1992). In total, 829 opportunistic
infections occurred in 8,989 CLL patients diagnosed 1994-2013. The most
common infection was Pneumocystis jirovecii pneumonia (PCP, IR 4.03 per
1,000 patient years), and relative to matched controls, risk of PCP was also
highest (IRR 114, 95% CI 58.7-252). Herpes zoster infections were the
second most common opportunistic infections (IR 2.94). Finally, fungal
infections with Candida and Aspergillus had an incidence of IR 1.66 and IR
1.20, respectively, and were associated with abysmal prognosis (CFR 33%
and 42%, respectively). Other opportunistic infections were rarer.
Conclusions: In these population-based studies we have established that
survival improved in CLL patients during the study period. This was largely
due to decreased CLL-related mortality. Importantly, admissions and
mortality due to infections decreased significantly over time. Populationbased studies are essential to evaluate the benefit and complications of new
treatments in real-world patients.Rannsóknarsjóður Háskóla Ísland