| 15641. |
- Meier, Karsten, 1991-
(författare)
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Identifying, characterizing, and targeting chlamydial virulence factors to unleash the power of host cell-autonomous immunity
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chlamydia trachomatis is the most common infectious cause of blindness and a prevalent bacterial agent of sexually transmitted infections, with an annual incidence exceeding 130 million cases. The current therapeutic approach to Chlamydia infections relies on broad-spectrum antibiotics. However, while generally effective, these antibiotics carry the risk of substantial collateral damage, for instance by promoting resistance in bystander pathogens and by adversely affecting commensal microbes. Hence, the development of a more sustainable, narrow-spectrum treatment would be advantageous. In this context, the bacterium’s highly specialized obligate intracellular lifestyle could offer a wealth of unique targets for intervention. This thesis specifically investigates the potential of harnessing the protective power of cell-autonomous immunity in our battle against Chlamydia.It is envisaged that the therapeutic exploitation of cell-autonomous immunity will initially necessitate three pivotal steps. Firstly, it will require identifying protective host cellular defense programs and counteracting virulence factors, which could serve as potential molecular targets. Secondly, it will be crucial to determine the molecular mechanisms by which the pathogen’s virulence factors suppress the host cellular defenses. Thirdly, pharmacological means to target the identified virulence factors or host cellular defense programs will need to be identified. This thesis outlines three independent projects, executed concurrently, to advance our knowledge at these three steps.The first project involved the implementation of an innovative molecular genetic screening approach, which was devised to reveal host cellular defense mechanisms that could effectively restrict the growth of C. trachomatis provided they were not actively suppressed by the pathogen. This investigation culminated in the discovery of a mutant C. trachomatis strain that lacks the ability to effectively evade xenophagy. Overall, this finding highlighted Chlamydia’s ability to evade this defense mechanism as a potential novel target for therapeutic intervention.The second project encompassed the molecular characterization of CpoS, a C. trachomatis virulence factor previously identified to counteract cell-autonomous immunity by inhibiting induction of type-I interferon responses and premature host cell death. The analyses revealed that CpoS manipulates host cellular membrane trafficking and suppresses host cellular type-Iinterferon responses through its interactions with the host factor Rab35.The third project involved a compound screening campaign that identified several novel selective anti-chlamydial compounds. Interestingly, one molecule exhibited reduced activity in xenophagy-deficient cells, implying a potential involvement of xenophagy in its mechanism of action.In summary, this research pinpointed xenophagy as a potential defensive mechanism against C. trachomatis, offered in-depth understanding of the operational mode of the virulence factor CpoS, and discovered new selective therapeutic alternatives, which in part utilize xenophagyin their mechanism of action. Consequently, this thesis provides a comprehensive overview of the transition from fundamental research to the more application-oriented domain of drug discovery and may inspire the development of more sustainable therapeutic strategies for the clinical handling of Chlamydia infections.
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| 15642. |
- Meili, Kaspar Walter, 1989-
(författare)
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Capability for broader cost-effectiveness in public health and social welfare : developing, valuing, and applyingcapability-adjusted life years Sweden (CALY-SWE)
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Spending in social welfare areas such as healthcare, wider public health, education, and social care consumes a major part of the public budget. Cost-effective resource allocation is a moral obligation towards both taxpayers and beneficiaries: tax money should be used efficiently, and it should be transparently accounted for. After all, economical management of resources is important for sustaining future prosperity and for addressing fundamental challenges such as climate change and demographic shift. In healthcare, cost‐effectiveness using quality-adjusted life years (QALYs) is a well-established tool to inform policymakers. Using cost per QALY implies that health-related quality of life (QoL), and not money, is an end on its own. Moreover, cost per QALY allows one to compare unrelated interventions by measuring the effects on the common QALY scale. However, for actors concerned with broader social welfare, such as the Swedish municipalities, QALYs may be less useful because their measurement focus is largely limited to health. Comparable outcome measures for broader social welfare are still sparsely available and employed, and a context-specific measure for Sweden is lacking. The aim of this thesis was to develop, value, and apply capability-adjusted life years Sweden (CALY‐SWE), a QoL outcome measure conceptually based on the capability approach, for broader social welfare and specific for Sweden.Within study 1, we organized a Delphi panel to select relevant capability attributes and then developed the phrasing for the questionnaire. The resulting questionnaire contains six attributes –health, social relations, financial situation & housing, security, occupation, and political & civil rights – each with three answer levels. The phrasing integrates an implicit threshold so that the sensitivity is focused on the lower range of the scale, thus incorporating equity considerations that relate to sufficientarianism and prioritarianism. In study 2, we developed a value set consisting of all quality weights for the 729 possible CALY-SWE states. We relied on health economic outcome methodology, namely hybrid modelling of discrete choice and time trade-off data that we collected in a cross-sectional web survey with representative sampling. This value set allows to aggregate the CALY-SWE answers into a single quality weight that can be used in cost‐effectiveness analysis to calculate CALYs. In study 3, we applied the CALY-SWE questionnaire and value set to describe the capability distribution in a cross-sectional representative sample of the Swedish population. In a framework of group comparisons, we estimated capability inequalities and shortfalls for different population groups. The results showed that there are capability inequalities for *disadvantage groups* as well as for groups with discriminative inequalities – *plurality groups*, for example between lower and higher education. For study 4, we applied CALY‐SWE in a cost‐effectiveness application to model the effects of a payroll tax reduction in Sweden from 2007 to 2016 (during the financial crisis) on young people not in employment, education, or training (NEET). The intervention was likely cost-effective from a societal perspective, but only with limited probability from a fiscal perspective, although definite statements regarding cost-effectiveness are challenging because a threshold value for a CALY is still lacking. The final chapter discusses the measure’s development, including normative choices, in relation to the Swedish social welfare and policy context, the capability framework as suggested by Amartya Sen, distributive justice, and other outcome measures in cost‐effectiveness evaluations. Important work remains – for example, assessing psychometric properties, developing the conceptualization of the 0 to 1 anchor scale for capability weights, and assessing a threshold value for a CALY. In conclusion, with the questionnaire development, value set elicitation, and demonstration of applications, important steps for CALY‐SWE were accomplished. Cost‐effectiveness evaluations in wider social welfare and public health using CALY-SWE are now possible.
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| 15643. |
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| 15644. |
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| 15645. |
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| 15646. |
- Meissner, Katja, et al.
(författare)
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Pilotprojekt ”Dendro-databas” i SEAD : April 2012-juni 2012
- 2012
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Pilotprojektet ”Dendro-databas” är ett samarbetsprojekt mellan det Nationella laboratoriet för vedanatomi och dendrokronologi vid Lunds universitet och SEAD-projektet vid Miljöarkeo-4logiska laboratoriet, Umeå universitet. Tillsammans arbetar man med utvecklingen av en da-tabas för dendrokronologiska data som kommer att hanteras och förmedlas via SEAD:s data-basverktyg. I detta arbete ingår både systemutveckling för att anpassa SEAD:s struktur för nya datamängder och inmatning av omfattande testdataserier.
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| 15647. |
- Meissner, Kristian, et al.
(författare)
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Predator-prey interactions in a variable environment : responses of a caddis larva and its blackfly prey to variations in stream flow
- 2009
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Ingår i: Annales Zoologici Fennici. - : Finnish Zoological and Botanical Publishing Board. - 0003-455X .- 1797-2450. ; 46:3, s. 193-204
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Predator-prey studies in streams have traditionally focused on mayfly-stonefly interactions in relatively constant flow conditions. In reality, however, lotic prey encounter multiple types of predators, most of which are restricted to low-velocity microhabitats. By contrast, some invertebrate prey may occur in very high current velocities. For example, many blackfly species are able to feed at velocities of 100 cm s(-1), whereas even moderate currents reduce the hunting efficiency of their invertebrate predators. The caddisfly larvae of the genus Rhyacophila, however, may be an exception to the pattern of reducing predator efficiency with increasing velocity. Using a combination of laboratory and field experiments and behavioral field observations, we examined the interaction between predatory Rhyacophila caddis larvae and larval blackflies along a velocity gradient of 20-120 cm s(-1). In laboratory experiments, Rhyacophila preferred currents slower than 50 cm s(-1) while blackflies exhibited a wide tolerance of currents and frequently occurred in currents exceeding 100 cm s(-1). In direct field observations, total activity and distance moved by Rhyacophila were similar at all current velocity regimes tested, but frequency of predation attempts on blackflies was lowest at the highest velocities (> 100 cm s(-1)). In a field colonization study, blackflies avoided substrates with the slowest velocities (< 40 cm s(-1)), as also did the caddis larvae. Only velocities approaching 100 cm s(-1) provide blackflies with refuge from predation by Rhyacophila. Being able to maneuver across a wide range of velocities, Rhyacophila may have more pervasive effects on their prey than other lotic invertebrate predators.
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| 15648. |
- Meister, Kadri, et al.
(författare)
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Luftföroreningshalter och akutbesök för astma och andra luftvägssjukdomar i Stockholm, Göteborg och Malmö 2001-2008 : projektrapport till Naturvårdsverket, hälsorelaterad miljöövervakning avtal 2150901
- 2012
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Denna studie inom den hälsorelaterade miljöövervakningen har genomförts på uppdrag av Naturvårdsverket för att belysa eventuella korttidseffekter av luftföroreningar på akutbesök för astma och alla sjukdomar i andningsorganen, vilka ofta medför ökad känslighet för luftföroreningar. Halternas samband med akutbesök för andningsorganens sjukdomar har tidigare studerats inom miljöövervakningen. För att underlätta jämförelser har metodiken anpassats till tidigare studier där betydelsen av halterna de två senaste dygnen beräknas. Övervakning av denna typ av direkta samband med halter i miljön är mindre känslig för trender och förändringar i diagnostik och vårdresurser än enklare epidemiologisk bevakning av antalet fall per år etc., eftersom totala antalet fall i sig kan påverkas av en rad olika typer av faktorer utan koppling till luftföroreningssituationen.Uppgifter om den skrivna befolkningens akutbesök under åren 2001 till och med 2008 för andningsorganens sjukdomar inklusive astma vid akutsjukhusen i StorStockholm (9 sjukhus), Göteborg och Mölndal respektive Malmö har inhämtats från Socialstyrelsens Patientregister. Uppgifterna från registret avser avidentifierade akutbesök med diagnoser dygn för dygn under perioden.Luftföroreningsdata i form av urbana bakgrundshalter har hämtats från Stockholm luft- och bulleranalys (SLB) vid miljöförvaltningen i Stockholm, Göteborgs miljöförvaltning respektive Malmö miljöförvaltning. Vi har studerat partikelhalten som PM10, avgashalten indikerad med kväveoxider (NOx) samt ozon. Vi har för första gången studerat effekterna för olika åldergrupper: barn (tom 18 år), vuxna (19-64 år) och äldre (from 65 år).Tidsserieanalyserna har utförts med Poisson-regression. I dessa analyser tas hänsyn till tidstrender, årstidsmönster, influensaperioder, väderförhållanden, pollenhalt, veckodag, helgperioder mm. De inkluderade luftföroreningarna är ozon, kvävedioxid och partiklar. Alla luftföroreningsvariabler kan ses som indikatorer på olika typer av luftföroreningar, och har simultant beaktats i de slutliga analyserna.Sambanden skiljer sig i några fall signifikant mellan studieområdena. För akutbesök för andningsorganen totalt och för astma alla åldrar fann vi kraftigare effekter av PM10 i Malmö. För kväveoxider (NOx) och akutbesök för andningsorganen totalt liksom för astma alla åldrar var den skattade effekten högre i Stockholm. Effekten av ozon på astma alla åldrar var lägre i Malmö.När resultaten vägdes ihop för de tre studieområdena beräknas att antalet akutbesök för andningsorganen totalt ökar med 1.4% (95% KI =0.0-2.9%) per 10 μg/m3 PM10, akutbesök för astma med 2.1% (95% KI= -0.1-4.3%) per 10 μg/m3, medan akutbesök för astma bland barn med 2.9% (95% KI=0.9- 4.8%) per 10 μg/m3.Motsvarande sammanvägda resultat för NOx visar en ökning av totala antalet akutbesök för andningsorganen med 0.7% (95% KI=-0.1-1.5 %) per 10 μg/m3, akutbesök för astma med 1.6% (95% KI=0.5-2.7%) samt akutbesök för astma bland barn med 1.7% (95% KI=0.4-3.1%) per 10 μg/m3. 2För ozon visar de sammanvägda resultat en ökning av totala antalet akutbesök för andningsorganen med 1.3% (95% KI=0.5-2.1%) per 10 μg/m3, akutbesök för astma med 1.7% (95% KI=0.0-3.4% ) samt akutbesök för astma bland barn med 1.8% (95% KI=0.2- 3.3%) per 10 μg/m3.Eftersom föroreningssituationen som indikatorerna representerar kan förändras med tiden, bör analyserna upprepas med viss periodicitet. Vi ser för Malmö att vissa effekter är säkerställt högre under den senare delen av studien. I framtiden kommer trendanalyser att kunna genomföras lämpligtvis genom att resultat för 3-5-årsintervall jämförs.
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| 15649. |
- Meister, Kadri, 1973-
(författare)
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On Methods for Real Time Sampling and Distributions in Sampling
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is composed of six papers, all dealing with the issue of sampling from a finite population. We consider two different topics: real time sampling and distributions in sampling. The main focus is on Papers A–C, where a somewhat special sampling situation referred to as real time sampling is studied. Here a finite population passes or is passed by the sampler. There is no list of the population units available and for every unit the sampler should decide whether or not to sample it when he/she meets the unit. We focus on the problem of finding suitable sampling methods for the described situation and some new methods are proposed. In all, we try not to sample units close to each other so often, i.e. we sample with negative dependencies. Here the correlations between the inclusion indicators, called sampling correlations, play an important role. Some evaluation of the new methods are made by using a simulation study and asymptotic calculations. We study new methods mainly in comparison to standard Bernoulli sampling while having the sample mean as an estimator for the population mean. Assuming a stationary population model with decreasing autocorrelations, we have found the form for the nearly optimal sampling correlations by using asymptotic calculations. Here some restrictions on the sampling correlations are used. We gain most in efficiency using methods that give negatively correlated indicator variables, such that the correlation sum is small and the sampling correlations are equal for units up to lag m apart and zero afterwards. Since the proposed methods are based on sequences of dependent Bernoulli variables, an important part of the study is devoted to the problem of how to generate such sequences. The correlation structure of these sequences is also studied. The remainder of the thesis consists of three diverse papers, Papers D–F, where distributional properties in survey sampling are considered. In Paper D the concern is with unified statistical inference. Here both the model for the population and the sampling design are taken into account when considering the properties of an estimator. In this paper the framework of the sampling design as a multivariate distribution is used to outline two-phase sampling. In Paper E, we give probability functions for different sampling designs such as conditional Poisson, Sampford and Pareto designs. Methods to sample by using the probability function of a sampling design are discussed. Paper F focuses on the design-based distributional characteristics of the π-estimator and its variance estimator. We give formulae for the higher-order moments and cumulants of the π-estimator. Formulae of the design-based variance of the variance estimator, and covariance of the π-estimator and its variance estimator are presented.
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| 15650. |
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