| 1. |
- Eriksson, Ulrika, 1972-
(författare)
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Contribution of polyfluoroalkyl phosphate esters (PAPs) and other precursor compounds to perfluoroalkyl carboxylates (PFCAs) in humans and the environment
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Per-and polyfluoroalkyl substances (PFAS) are anthropogenic compounds that have been spread all over the world. The use of fluorotelomer compounds, short-chained homologues, and other PFASs with perfluorinated moieties has emerged recent years. One of these emerging compound classes is polyfluoroalkyl phosphate esters (PAPs), which have the ability to degrade into persistent PFCAs.The aim of this thesis was to assess the contribution of PAPs and other precursors to the exposure of PFCAs to humans and the environment. The main objective was to analyze a wide range of PFAS in human serum, wild bird eggs, indoor dust, waste water, and sludge. There was a significant contribution from selected precursors to the total amount of PFASs in the abiotic compartments indoor dust, waste water, and sludge. Levels of PAPs found in house dust exceeded those of PFCAs and perfluorosulfonic acids (PFSAs), revealing PAPs as a world-wide important exposure source.A net increase was during waste water treatment was observed for several PFASs in Swedish waste water treatment plants. Together with presence of precursor compounds and intermediates in the influent water and the sludge, this suggest that degradation of PFCA precursors contributed to the increase of PFCAs. Detection of precursors in human serum, together with slow declining trends of PFCAs, revealed an ongoing exposure of PFCAs to the general population of Australia. The diPAPs and the FTSAs were also detected in raptor bird eggs from Sweden from both the terrestrial and the freshwater environment. The precursors concentrations and patterns observed reveal that current regulatory measures are insufficient for the purpose of protecting humans and the environment from PFASs exposure.
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| 2. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 3. |
- Källsten, Liselott, 1992-
(författare)
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In vitro and in vivo studies on the toxicology of di-n-butyl phthalate (DBP) : Effects on reproductive, endocrine, and immune systems
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chemical pollution is an increasing societal problem and has a major impact on human and environmental health. One important source of chemical pollution is plastic, which contains many different compounds with often largely unknown hazards. Phthalates are one group of chemicals in plastic that has been associated with several adverse effects in humans, particularly reproductive system impairments. Studies have also suggested a link between exposure to phthalates and negative effects on the immune system. One of the most widely used phthalates is di-n-butyl phthalate (DBP), which is frequently detected in humans and the environment. DBP has been associated with decreased male fertility and reduced levels of testosterone. However, the mechanisms behind these anti-androgenic effects are not entirely understood, and most studies have focused only on developmental exposure.This thesis aims to, for the first time, investigate persistent effects on the reproductive and immune systems of adult male mice after exposure to DBP. Adult male mice were orally exposed to DBP (0, 10 or 100 mg/kg/day) for 5 weeks. A persistent and significant decrease in testicular testosterone levels was shown together with an increase in the levels of several steroidogenic enzymes 1 week after the conclusion of exposure. The decrease in testosterone may be related to the demonstrated increase in oxidative stress, which may affect enzyme activity. Additional mechanistic studies were conducted in the human adrenal cell line H295R. The testosterone levels decreased also in vitro; however, the levels of several steroidogenic enzymes in the cells decreased, which is in contrast with the in vivo study. Several additional steroid hormones were affected in vitro, but not in vivo. The animal study further revealed significantly increased levels of the key testicular proteins DAZL, vimentin, SOX9, and SULT1E1.Moreover, a persistent immunosuppressive effect was demonstrated in the DBP-exposed mice, supporting previous data indicating that endocrine disruptors can affect the immune system. DBP-induced leukopenia, reduced numbers of T helper cells, and increased levels of immunosuppressive cells were observed. In addition, the distribution of two main DBP metabolites to three proposed target tissues (liver, testes, and adipose tissue) was examined, and the presence of the metabolites was confirmed 24 h after the final dose. The glucuronidation pattern in the mice was shown to be more similar to that previously observed in humans than in rats.In conclusion, the results in this thesis support that the testes and immune system are key targets for DBP-induced toxicity. DBP decreased the testosterone levels both in vivo and in vitro, but certain differences in the effects on steroidogenesis were observed between the experimental models. Further studies are required to determine the No Observed Adverse Effect Level (NOAEL) for the effects identified in the animal model and to understand the underlying mechanisms completely.
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| 4. |
- Pennells, Lisa, et al.
(författare)
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Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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| 5. |
- Siverskog, Jonathan, 1988-
(författare)
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Opportunity cost in healthcare priority setting
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The resources available for the public provision of health care are not unlimited. Cost-effectiveness evidence on new healthcare interventions can help us prioritise in order to use scarce resources wisely, but to interpret cost-effectiveness evidence, it may appear as if we must make trade-offs between life and money. This is not so. If we are able to quantify the health improvements that resources would or could have generated in alternative use, a decision about providing or denying treatment can instead be framed as a trade-off between health gained and health forgone. In this thesis, I seek to provide a more robust basis for this way of reporting and interpreting cost-effectiveness evidence.In Chapter II, I discuss the definition of opportunity cost in economic evaluation. The opportunity cost of providing an intervention is what we must give up to provide it. More precisely, it is typically defined as the value of the best alternative forgone. In economic evaluation of health care, opportunity cost has been understood in terms of the least cost-effective, currently funded intervention, which should be displaced when funding new interventions subject to a fixed budget. I show that alternative uses forgone may be neither currently funded nor well-defined, which implies that we should not look to cost-effectiveness evidence on specific interventions for information on opportunity cost. Further, identifying a best alternative use assumes that priority setting is based on objectives that can be summarised into a single measure of value. If economic evaluation is used to inform trade-offs between one measure of value (e.g., quality-adjusted life years, QALYs) and other, unquantified objectives, I suggest that it would be more appropriate to define opportunity cost as value in expected alternative use.To quantify opportunity cost as health forgone, we need evidence on the health that resources would or could have generated in alternative use. In Chapter III, I use panel data on health spending and life expectancy in Swedish regions to estimate the marginal cost of producing a QALY. My findings imply that Swedish health care can produce health at a marginal cost of SEK 180,000 per QALY, which could be used as an expectation on how productive health spending would be in alternative use. I discuss methodological issues with this approach and identify some credibility problems with selection-on-observables strategies plaguing this and similar research to date. I address (some of) these problems by assessing coefficient stability and the causal mechanisms between healthcare resource use and health outcomes, using a second panel on hospital bed capacity and mortality. This analysis finds that health could be gained at a cost of SEK 420,000 per QALY by providing more hospital beds.To illustrate the role of this evidence in healthcare priority setting, Chapter IV considers how it could have been used to inform decision making in a case of pharmaceutical reimbursement. I propose that economic evaluation report cost-effectiveness evidence as QALYs forgone per QALY gained. This frames a decision about providing or denying treatment as a judgement on the relative priority of QALYs gained and QALYs forgone, which is more transparent about a trade-off between equity and efficiency than deciding whether the monetary cost per QALY is too high. Framing decisions as health gained versus health forgone could also lead to better decision making by making opportunity costs more salient to decision makers and the reason for sometimes denying costly treatments easier to communicate.In summary, cost-effectiveness evidence can be used to achieve the theoretical objective of health maximisation, but economic evaluations rarely report opportunity costs explicitly as health forgone. This thesis provides the practical means to be explicit and implications for the definition of opportunity cost and the interpretation of cost-effectiveness evidence when health maximisation is not the sole objective of healthcare priority setting.
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| 6. |
- Ahlsten, Nanna, 1982-
(författare)
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Transition metal-catalysed isomerisation of allylic alcohols : Applications to C−C, C−F and C−Cl bond formation
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The focus of this thesis has been to develop selective and atom-economical methods for carbon-carbon and carbon-heteroatom bond formation, and to some extent improve on existing findings in this area. More specifically, methods for the catalytic generation of enolates from allylic alcohols and their in situ functionalisation with electrophilic reagents are described. In the first part of this thesis, a method for the Rh-catalysed redox-isomerisation of allylic alcohols into carbonyl compounds under environmentally benign conditions is described. The reaction takes place at room temperature, in the absence of acids or bases, using water as the only solvent, and it is applicable to both primary and secondary allylic alcohols.The second part describes the combination of an isomerisation reaction of allylic alcohols with a C−C bond formation, catalysed by a rhodium complex. In this way, allylic alcohols were coupled with aldehydes and N-tosylimines to give aldol and Mannich-type products. In addition to allylic alcohols, homoallylic and bishomoallylic alcohols could be used as enolate precursors, and this is the first report where the latter two substrate types have been used in such a reaction. In the remaining parts of the thesis, an iridium-catalysed isomerisation of allylic alcohols has been combined with an electrophilic halogenation step to provide a conceptually new method for the synthesis of α-halogenated carbonyl compounds. In this way, α-fluoro and α-chloroketones have been synthesised as single constitutional isomers, with the regiochemistry of the final products determined by the position of the double bond in the allylic alcohols. The reactions are tolerant to air, run in water-organic solvent mixtures, and proceed at room temperature.
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| 7. |
- Lauren, Ida, et al.
(författare)
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Long-term SARS-CoV-2-specific and cross-reactive cellular immune responses correlate with humoral responses, disease severity, and symptomatology
- 2022
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Ingår i: Immunity, Inflammation and Disease. - : John Wiley & Sons. - 2050-4527. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cellular immune memory responses post coronavirus disease 2019 (COVID-19) have been difficult to assess due to the risks of contaminating the immune response readout with memory responses stemming from previous exposure to endemic coronaviruses. The work herein presents a large-scale long-term follow-up study investigating the correlation between symptomology and cellular immune responses four to five months post seroconversion based on a unique severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific peptide pool that contains no overlapping peptides with endemic human coronaviruses. Methods: Peptide stimulated memory T cell responses were assessed with dual interferon-gamma (IFN gamma) and interleukin (IL)-2 Fluorospot. Serological analyses were performed using a multiplex antigen bead array. Results: Our work demonstrates that long-term SARS-CoV-2-specific memory T cell responses feature dual IFN gamma and IL-2 responses, whereas cross-reactive memory T cell responses primarily generate IFN gamma in response to SARS-CoV-2 peptide stimulation. T cell responses correlated to long-term humoral immune responses. Disease severity as well as specific COVID-19 symptoms correlated with the magnitude of the SARS-CoV-2-specific memory T cell response four to five months post seroconversion. Conclusion: Using a large cohort and a SARS-CoV-2-specific peptide pool we were able to substantiate that initial disease severity and symptoms correlate with the magnitude of the SARS-CoV-2-specific memory T cell responses.
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| 8. |
- Lee, Yeh Chen, et al.
(författare)
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Symptom burden and quality of life with chemotherapy for recurrent ovarian cancer : the Gynecologic Cancer InterGroup-Symptom Benefit Study
- 2022
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Ingår i: International Journal of Gynecological Cancer. - : BMJ Publishing Group. - 1048-891X .- 1525-1438. ; 32:6, s. 761-768
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Tidskriftsartikel (refereegranskat)abstract
- Objective The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with >= 3 lines of chemotherapy (PPS-ROC >= 3). Methods Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3-4 weeks until progression. Participants were classified symptomatic if they rated >= 4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of <= 3 in at least half of the symptomatic items at baseline. Improvement in HRQL was defined as two consecutive scores >= 10 points above baseline in the QLQ-C30 summary score scale (range 0-100). Results Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC >= 3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC >= 3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p<0.0001). Improvements in HRQL were reported by 77/448 (17%) with PRR-ROC and 61/301 (20%) with PPS-ROC >= 3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline. Conclusion Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants.
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| 9. |
- Ullah, Shahid, 1977-
(författare)
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Improved analytical methods for perfluoroalkyl acids (PFAAs) and their precursors – a focus on human dietary exposure
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Per- and polyfluoroalkyl substances are a large group of global environmental contaminants. They can be divided into two sub-groups, 1) perfluoroalkyl acids (PFAAs) and 2) so called precursors, i.e. compounds that can potentially be transformed to form PFAAs. PFAAs are today ubiquitous in wildlife and humans. Food and drinking water are assumed to be the dominant human exposure pathways for PFAAs.The main aim of this doctoral thesis was to develop highly sensitive and fully validated analytical methods for the determination of a range of PFAAs and selected precursors in dietary samples. The methods were based on liquid chromatography coupled to mass spectrometry. Samples were extracted by solvent extraction followed by a cleanup step employing solid phase extraction. The cleanup step could at the same time be used as a fractionation of ionic PFAAs and neutral precursors.Paper I and II describe the development of methods for simultaneous analysis of three groups of PFAAs including perfluoroalkyl phosphonic acids (PFPAs) in drinking water and food. Methyl piperidine was used as ion pairing agent, leading to highly sensitive analysis of PFPAs. A first screening of tap water samples and different food items revealed that human dietary exposure to PFPAs in Europe is currently not of concern.A novel method for simultaneous analysis of perfluoroalkyl carboxylic acids (PFCAs) and polyfluoroalkyl phosphate esters (PAPs) in food and packaging materials is described in paper III. Targeted food samples and their packaging were analyzed. The results showed that PAPs may contribute to human exposure to PFCAs. In paper IV temporal trends (1991-2011) of perfluorooctane sulfonic acid (PFOS) and its precursors in herring were investigated. Rapidly decreasing trends were found for precursors, whereas PFOS did not show a significant change over time. Precursors in fish may have played an important role for human exposure to PFOS in the 1990s but are probably negligible today.
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| 10. |
- Alvarsson, Jonathan, 1981-
(författare)
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Ligand-based Methods for Data Management and Modelling
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Drug discovery is a complicated and expensive process in the billion dollar range. One way of making the drug development process more efficient is better information handling, modelling and visualisation. The majority of todays drugs are small molecules, which interact with drug targets to cause an effect. Since the 1980s large amounts of compounds have been systematically tested by robots in so called high-throughput screening. Ligand-based drug discovery is based on modelling drug molecules. In the field known as Quantitative Structure–Activity Relationship (QSAR) molecules are described by molecular descriptors which are used for building mathematical models. Based on these models molecular properties can be predicted and using the molecular descriptors molecules can be compared for, e.g., similarity. Bioclipse is a workbench for the life sciences which provides ligand-based tools through a point and click interface. The aims of this thesis were to research, and develop new or improved ligand-based methods and open source software, and to work towards making these tools available for users through the Bioclipse workbench. To this end, a series of molecular signature studies was done and various Bioclipse plugins were developed.An introduction to the field is provided in the thesis summary which is followed by five research papers. Paper I describes the Bioclipse 2 software and the Bioclipse scripting language. In Paper II the laboratory information system Brunn for supporting work with dose-response studies on microtiter plates is described. In Paper III the creation of a molecular fingerprint based on the molecular signature descriptor is presented and the new fingerprints are evaluated for target prediction and found to perform on par with industrial standard commercial molecular fingerprints. In Paper IV the effect of different parameter choices when using the signature fingerprint together with support vector machines (SVM) using the radial basis function (RBF) kernel is explored and reasonable default values are found. In Paper V the performance of SVM based QSAR using large datasets with the molecular signature descriptor is studied, and a QSAR model based on 1.2 million substances is created and made available from the Bioclipse workbench.
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