| 1. |
- Holmbom, Martin, 1984-
(författare)
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Clinical Impact of Bloodstream Infections – Characterization, Risk factors and Outcome
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bloodstream infection (blood poisoning) and antibiotic resistance are increasing worldwide, and already cause the loss of millions of human lives each year. According to the World Health Organisation (WHO), bloodstream infections (BSIs) represent 20% of global mortality on a par with cardiac infarct, stroke, and major trauma. BSI may occur when bacteria from a focus of infection gain access to the circulation (bacteraemia). BSIs are usually divided into two subclasses: community- and hospital-onset infections, since disease this involves different patient groups, types of bacteria, and reasons for infection. Compared to other countries, Sweden has been fortunate in having a relatively low death rate from BSI and low antibiotic resistance. However, as our lifestyle changes, the age of the population increases with more disease as a result, and as the healthcare system responds, death from infection and antibiotic resistance are on the increase. It is important that we recognise ”warning symptoms” if we are to manage BSIs correctly and initiate effective treatment. It is difficult to design individualised empirical treatment, so it is very important to be aware of risk factors for BSI and local resistance patterns, and to have an effective management programme. Bacterial resistance to antibiotics is an increasing problem, especially in bowel organisms that can cause infections that are very difficult to treat. In short, antibiotic resistance arises as a result of evolutionary processes where bacteria protect themselves by developing resistance genes. These genes can be exchanged between similar organisms or transmitted to others that in turn cause resistant infection. The use of antibiotics leads to an evolutionary/selection process leading to resistance in bacteria, both normal and pathogenic, enabling resistant organisms to survive, thrive, and go on to cause infection. Antibiotic resistance is a threat to global health. This thesis aims to increase our awareness of a large group of patients who suffer bloodstream infection. BSIs are increasing globally, and the death toll is high. Antibiotic resistance is an increasing threat to the health of the population, and we are inundated by alarming reports of resistance getting out of control. What is the situation in Sweden, and can we identify risk factors for BSI and mortality? In Study I, our aim was to study the incidence and mortality of BSI in Östergötland. To be able to do this, a large patient population stretching over several years was required. The study design was thus population-based in the form of an observational cohort study where all blood culture results from 2000 to 2013 were analysed, and evaluated from clinical data. A total of 109,938 results were analysed resulting in 11,480 BSIs. We saw that the incidence of BSI increased by 64% (mostly community-onset BSIs). We also saw that mortality increased by 45%. These results illustrate the importance of nationwide cooperation to combat the increasing problem of BSI and its mortality, and the establishment of a nationwide BSI register. The aim of Study II was to assess resistance development in Östergötland and its relationship to mortality. A total of 9,587 microorganisms were analysed between 2008 and 2016. We observed an increase in quinolone resistance (3.7-7.7%) and cephalosporin resistance (2.5-5.2%) amongst Enterobacteriaceae. We then looked at BSIs caused by multiresistant bacteria showing a total of 245 cases (2.6%); an increase of 300%. Despite this, we did not see an increased mortality in this group. There are several possible explanations for the increase in BSI mortality of which antibiotic resistance is a predominant factor globally. We were unable to show this in our study, even so mortality is increasing and is currently at a high level. In Study III we therefore analysed risk factors associated with death during a community-acquired BSI, focusing on preliminary prehospital and hospital management. In a retrospective case-control study on 195 deaths matched 1:1 regarding age, gender, and microorganism, with 195 survivors (controls). Results showed that many patients had contacted the primary healthcare system because of infection before they became severely ill, and that the strongest affectable risk factor for death was delay (>24h) between primary healthcare visit and admission to hospital. This shows the need for increased awareness in society and amongst the medical profession of those patients at risk and symptoms that should raise the alarm, leading to more rapid treatment. In Studies I and II we found an increase in both BSIs and mortality, we also saw an increase in antibiotic resistance and multiresistant bacteria, mainly ESBL-producing E. coli. On the other hand, we did not see any coupling between multiresistance and mortality in this Swedish population. E. coli is a gram-negative bacteria that causes most BSIs. Since E. coli is predominantly a urine tract pathogen, Study IV aimed to study BSIs caused by ESBL-producing E. coli originating from the urinary tract. We studied the prevalence of E. coli clones, resistance genes and risk factors, as well as any signs of increased mortality from ESBL-producing E. coli compared to sensitive E. coli. Our main finding was a surprisingly low mortality from ESBL-producing E. coli (3%). Most patients in the ESBL-producing E. coli group received inadequate antibiotic treatment for at least 48h, but we did not see any sign of increased mortality or risk for serious sepsis with circulatory failure in this group. This finding is interesting and opens up for new studies on virulence factors and immunological factors that govern the immune response to BSI. The implementation of cost-effective monitoring systems including clinical microbiological epidemiology and early identification of BSI, together with information campaigns aimed at the public as well as healthcare personnel regarding patients at risk and symptoms giving cause for alarm, should lead to a radical reduction in morbidity and mortality from BSI. This requires new diagnostic tools to individualise both antibiotic treatment and targeted management based on microorganism virulence factors. Modernisation of the medical journal system with algorithms aimed at early identification of risk patients and automated suggestions for empirical antibiotic treatment based on antibiotic resistance seen in previous cultures and local resistance patterns, would certainly improve management. Furthermore, new immunological tests showing the type of immunological reaction to a serious BSI will lead to individualised immunotherapy that, together with antibiotic treatment, will further improve patient care in this important group.
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| 2. |
- Ljungström, Viktor, 1986-
(författare)
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Exploring next-generation sequencing in chronic lymphocytic leukemia
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Next-generation sequencing (NGS) techniques have led to major breakthroughs in the characterization of the chronic lymphocytic leukemia (CLL) genome with discovery of recurrent mutations of potential prognostic and/or predictive relevance. However, before NGS can be introduced into clinical practice, the precision of the techniques needs to be studied in better detail. Furthermore, much remains unknown about the genetic mechanisms leading to aggressive disease and resistance to treatment. Hence, in Paper I, the technical performance of a targeted deep sequencing panel including 9 genes was evaluated in 188 CLL patients. We were able to validate 143/155 (92%) selected mutations through Sanger sequencing and 77/82 mutations were concordant in a second targeted sequencing run, indicating that the technique can be introduced in clinical practice. In Paper II we screened 18 NF-κB pathway genes in 315 CLL patients through targeted deep sequencing which revealed a recurrent 4 base-pair deletion in the NFKBIE gene. Screening of NFKBIE in 377 additional cases identified the mutation in ~6% of all CLL patients. We demonstrate that the lesion lead to aberrant NF-κB signaling through impaired interaction with p65 and is associated with unfavorable clinical outcome. In Paper III we sought to delineate the genetic lesions that leads to relapse after fludarabine, cyclophosphamide, and rituximab treatment. Through whole-exome sequencing of pre-treatment and relapse samples from 41 cases we found evidence of frequent selection of subclones harboring driver mutations and subsequent clonal evolution following treatment. We also detected mutations in the ribosomal protein RPS15 in 8 cases (19.5%) and characterization of the mutations through functional assays point to impaired p53 regulation in cells with mutated RPS15. Paper IV aimed at characterizing 70 patients assigned to three major subsets (#1, #2, and #4) through whole-genome sequencing. Besides recurrent exonic driver mutations, we report non-coding regions significantly enriched for mutations in subset #1 and #2 that may facilitate future molecular studies. Collectively, this thesis supports the potential of targeted sequencing for mutational screening of CLL in clinical practice, provides novel insight into the pathobiology of aggressive CLL, and demonstrates the clinical outcome and cellular effects of NFKBIE and RPS15 mutations.
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| 3. |
- Duvetorp, Albert, 1980-
(författare)
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Different Aspects of Psoriasis : Comorbidity, Comedication and Disease Biomarkers
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Psoriasis is a common heterogeneous inflammatory disease with its predominant manifestation occurring in the skin. The impact of this disease, however, extends far beyond the skin surface. During the last decades, mounting scientific evidence of psoriasis disease impact on quality of life, stigmatization and comorbidity has led to the predominant view that psoriasis care needs a holistic approach. Epidemiological research is needed to visualize the greater picture whereas research on disease pathomechanisms can provide answers to disease evaluation challenges, facilitate development of new treatments, and provide insights into mechanistical bridges explaining comorbidity occurrence. In study I of this thesis, serum S100A8/A9 was evaluated as a possible biomarker of psoriasis skin disease activity. Dramatic reductions in S100A8 and S100A9 and S100A8/A9 heterocomplex levels were found in lesional psoriasis skin after NB-UVB treatment without any significant reduction occurring in serum. Study II was designed as a retrospective, cross-sectional population study including the adult population of the county of Jönköping. The odds of having pharmacologically treated depression among individuals with psoriasis was compared to the odds of the background population. Psoriasis was associated with an elevated depression risk. Depression was more prevalent among women (both in the background population and among individuals with psoriasis). Young age was associated with higher odds for depression among individuals with psoriasis. Study III was based on the same study population as study II. In this study the comedication burden of individuals with psoriasis was compared to the background population. Comedication assessed were prescription drugs used to treat comorbidity associated with psoriasis in previous scientific publications. Patients with psoriasis were found to have a high comedication burden. Patients receiving systemic treatment for psoriasis had a higher number of different dispensed drugs suggesting that severe disease implies a higher risk of comorbid disease. Study IV was an exploratory study assessing numerous potential biomarkers for psoriasis disease activity. Extensive Luminex analysis of skin and serum samples collected during study I was performed. No serum mediator (potential biomarker of disease activity) showed a significant change after NB-UVB (following correction for multiple testing). In skin, NB-UVB had effects on mediators of the Th17 pathway and multiple chemokines but also previously undescribed or less explored disease mediators. Study II and III suggest that comorbidity and its comedication is common among Swedish psoriasis patients in contact with the health care system. This research reinforces the perception that a holistic approach is needed when treating patients with psoriasis. Behind the failure to identify a biomarker for skin disease activity in study I and IV lurks the questions to how, if or when inflammation in the skin affects systemic inflammation and in extension comorbid disease.
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| 4. |
- Nilsson, R. Anders, 1976-
(författare)
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Dangerous Liaisons : Why Ex-Combatants Return to Violence. Cases from the Republic of Congo and Sierra Leone
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- After disarming and demobilizing, why do some ex-combatants re-engage in organized vio-lence, while others do not? Even though former fighters have been identified as a major source of insecurity in post-civil war societies due to their military know-how, there have been few efforts to systematically examine this puzzle. This study fills this research gap by comparing the presence or absence of organized violence in different ex-combatant communi-ties – all the former fighters that used to belong to the same armed faction and who share a common, horizontal identity based on shared war-and peacetime experiences. It does so by analyzing six ex-combatant communities in two countries: ex-Cobra, Cocoye and Ninja in the Republic of Congo and ex-AFRC, CDF and RUF in Sierra Leone. More specifically, three concepts – remarginalization (former fighters’ lack of political influence, personal security or economic assistance), remobilizers (individuals who have the will, capacity and skills to coordinate organized violence in a post-conflict setting) and relationships (whether or not remobilizers share social or material bonds, conducive for war, with ex-combatant communi-ties and each other) – are applied to the six cases, in order to explain why relatively many former CDF, Cobra, Ninja and RUF fighters resorted to violence, while no or hardly any ex-AFRC and Cocoye combatants did the same. Contrary to assumptions found in previous research, this study finds that structural factors, relating to remarginalization, have little ex-planatory value in themselves. Being a rule, rather than an exception, remarginalization can best be understood as a background variable, creating conducive conditions for violence to take place. Instead, the main determinants of ex-combatant violence are whether former fight-ers have access to regional or domestic elites in the market for experienced fighters and to second-tier individuals – such as former mid-level commanders – who can act as intermediar-ies between the two. By utilizing relationships based on selective incentives and social net-works, these two kinds of remobilizers are able to generate the needed enticements and feel-ings of affinity, trust or fear, to convince ex-combatants to resort to arms. These findings demonstrate that the outbreak of ex-combatant violence can only be understood by more clearly incorporating an actor perspective, focusing on three levels of analysis: the elite, mid-level and grass-root.
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| 5. |
- Sjödin, Fredrik, 1978-
(författare)
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Noise in the preschool : health and preventive measures
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is based on noise recordings and health evaluations carried out at preschools in the northern part of Sweden. Sound level recordings were made on individuals and by use of stationary devices in dining rooms and play halls. Health evaluations were based on ratings by use of questionnaires and by analyses of cortisol.The average equivalent individual noise exposure was 71 dB(A). The average equivalent noise levels in the dining room and playing halls were 64 dB(A). The hearing loss of the employees was significantly higher for the frequencies tested than in an unexposed control group. Symptoms of tinnitus were reported among 31% of the employees. Noise annoyance was rated as somewhat to very annoying, and the voices of the children were the most annoying noise source. The dB(A) level and fluctuations of the noise exposure were significantly correlated with the number of children per department. Stress and energy output were pronounced among the employees. About 30% of the staff experienced strong burnout syndromes. Mental recovery was low as indicated by noise fatigue and high levels of stress after work. Increased cortisol levels during work were associated with higher number of children present at the department.An essential finding of the thesis was that noise and noise sources may impair the pedagogic work, thereby increasing the work load of employees. It is concluded that noise exposure in the preschool, isolated or in combination with other stressors, plays a fundamental role in the building up of acute as well as long term stress. An intervention study implementing six acoustical and seven organizational measures was tested, aimed to improve the noise situation in the departments. Acoustical measures improved the noise situation as well as the rated noise experiences better than the organizational measures.
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| 6. |
- Sundling, Catherine, 1962-
(författare)
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Overall Accessibility of Public Transport for Older Adults
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is based on four studies that explore accessibility for older adults during whole trips by public transport. The overall goal was to gain knowledge of the interrelationships among key variables and to develop a conceptual model of the overall accessibility of public transport. More specifically, the research goals were: (a) to explore links among the key variables postulated to be involved in overall accessibility and to explore the links between these variables and railway accessibility; (b) to gain a deeper understanding of links between critical incidents in traveling and travel behavior decisions; and (c) to develop a conceptual model of overall accessibility. The key variables contributing to overall accessibility are functional ability (depending partly on the person’s functional limitation or disease), travel behavior, and barriers encountered during whole-trip traveling involving train. Respondents with more than one functional limitation or disease reported lower functional ability than did those with only one such limitation and respondents with low functional ability were less frequent travelers than were those with high functional ability. Frequent travelers reported railway accessibility to be better than did those who traveled less frequently. The main barriers were ticket cost and poor punctuality, but respondents with the lowest functional ability attributed the barriers encountered to their own health. The critical incidents most frequently reported were found in the categories “physical environment onboard vehicles” and “physical environment at stations or stops”, as well as in the “pricing and planning during ticketing” phase of the trip. Five themes of reactions to critical incidents were identified that had resulted in behavior change: firm restrictions, unpredictability, unfair treatment, complicated trips, and earlier adverse experiences. A conceptual model of overall accessibility was developed, grounded in the empirical research results. This model is summarized in the following propositions: Overall accessibility is a reciprocal relationship among the barriers/facilitators encountered, functional ability, and travel behavior. Accessibility emerges in the person–environment interaction. To understand accessibility, past experiences and future expectations should both be considered, because both will guide travel decisions.
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| 7. |
- Szychowska, Malina, 1991-
(författare)
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Effects of visual load on auditory processing
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In daily life, people need to be able to focus on a task while ignoring any task-irrelevant background noise. For example, people who work in an open-space office may have to work on a report while ignoring the background talk among co-workers. Theories of attention argue that processing of task-irrelevant auditory information should become attenuated when attentional capacity is exhausted by task-relevant stimuli, for example a visual task. According to early-filter theory, top-down attenuation of auditory responses is possible at various stages of the auditory pathway through multiple recurrent loops. Furthermore, the adaptive filtering model of selective attention suggests that filtering occurs early when concurrent visual tasks are demanding (e.g., high load) and late when tasks are easy (e.g., low load).The main aim of this thesis was to investigate whether auditory processing is attenuated during concurrent visual load manipulation, and if so, at which stage of the auditory pathway. Recurrent loops that are present throughout the entire auditory pathway should allow top-down modulation of even earliest responses, especially when accompanied by a highly demanding task. Recording these auditory responses during concurrent visual tasks with different levels of load could potentially show at which stages of auditory processing the filtering happens when the task demands are high or low, or there is no task at all.This thesis tested the effects of visual load manipulation on the responses originating from different stages of the auditory pathway: mismatch negativity (MMN) to duration in Study I, MMN to frequency in Study III, auditory steady-state responses (ASSRs) to a 40-Hz modulation frequency in Study IV, and ASSRs to 20-, 40-, and 80-Hz modulation frequencies in Study V. Additionally, Study II compared different control conditions (cascade vs. no-repetition control) for evoking MMN to find a design that reduces confounds in the MMN. Results of Study II showed that cascade and no-repetition control are comparable control conditions for evoking MMN.For the effects of visual load manipulation on auditory MMN (low vs. high load), results showed moderate evidence for the effect of load on duration MMN and moderate evidence for no effect of load on frequency MMN. However, results for the duration MMN might be confounded by physical differences between the low load and high load conditions in the visual task, and by a biased oddball paradigm used to evoke the MMN. Thus, it is most likely that auditory MMN is not affected by visual load (low vs. high).For the effects of visual load on ASSRs (no, low, and high load), results showed moderate to strong evidence for no effects of load manipulation on ASSRs, but some comparisons were inconclusive. The convincing evidence obtained in Studies IV and V points to the robustness of ASSRs against visual load manipulation.Because it is most likely that neither MMN nor ASSRs are affected by visual load manipulation, results presented in this thesis support the idea that attentional resources are modality specific. Because it is possible that filtering occurs at one stage of auditory processing and does not change with the concurrent task demands, the present results do not rule out the early-filter theory. However, results are inconsistent with the adaptive filtering model because filtering of task-irrelevant responses does not vary with the demands of the concurrent task.
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| 8. |
- Zhang, Qi, 1995-
(författare)
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Ion escape from Mars
- 2023
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- When the solar wind reaches the Mars obstacle, mass loading by planetary ions slows down the solar wind and raises the bow shock. The Martian atmosphere is undergoing the a scavenging by the solar wind without the protection of a global magnetic field. Atmospheric escape is an important process for the evolution of the Martian climate. For present Mars, the dominant escape of atmospheric neutrals is through four channels: Jeans escape, photochemical reactions, sputtering and electron impact ionization. Ions above the exobase get accelerated by the solar wind electric field and can escape.We here apply a new method for estimating heavy ion (O+, O+2, and CO+2) escape rates at Mars, which combines a hybrid model and observations. We use observed upstream solar wind parameters as input for a hybrid plasma model, where the total ion upflux at the exobase is a free parameter. We then vary this ion upflux to find the best fit to the observed bow shock location. This method gives us a self-consistent description of the Mars-solar wind interaction, which can be used to study other properties of the solar wind interaction besides escape.
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| 9. |
- Östholm Balkhed, Åse, 1972-
(författare)
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Extended-Spectrum ß-Lactamase-Producing Enterobacteriaceae : Antibiotic consumption, Detection and Resistance Epidemiology
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ESBL-producing Enterobacteriaceae are emerging worldwide and they are frequently multi-drug resistant, thus limiting treatment options for infections caused by these pathogens.The overall aim of the thesis was to investigate ESBL-producing Enterobacteriaceae in a Swedish county.First, we developed a molecular method, a multiplex PCR assay for identification of SHV, TEM and CTX-M genes in clinical isolates of Enterobacteriaceae with an ESBL phenotype.From 2002 until the end of 2007 all isolates of ESBL-producing Enterobacteriaceae in Östergötland, Sweden were further investigated. The prevalence of ESBL-producing Enterobacteriaceae was low, <1%, but increasing,while the antibiotic consumption remained unchanged. CTX-M enzymes, particularly CTX-M group 1, dominate in our region as well as in the rest of Europe.Furthermore, we have investigated antimicrobial susceptibility by performing MIC-testing in a large, well-characterized population of CTX-M-producing E. coli. Only three oral antimicrobial agents (fosfomycin, nitrofurantoin and mecillinam) demonstrated susceptibility above 90%. High susceptibility, >90%, was also demonstrated for carbapenems, colistin, tigecycline and amikacin. Sixty-eight per cent of ESBL-producing E. coli was multi-resistant, and the most common multi-resistance pattern was the ESBL phenotype with decreased susceptibility to trimethoprim, trimethoprim-sulfamethoxazole, ciprofloxacin, gentamicin and tobramycin. Isolates belonging to CTX-M group 9 are generally more susceptible to antibiotics than the CTX-M group 1-producing E. coli. Finally, a prospective multicentre case-control study examined the prevalence of ESBL-producing Enterobacteriaceae in faecal samples before and after travel abroad and the risk factors of acquisition. Sixty-eight of 226 travellers (30%) had ESBL-producing Enterobacteriaceae in the faecal flora. The geographical area visited had the highest impact on acquisition, with highest the risk for travellers visiting the Indian subcontinent, followed by Asia and Africa north of the equator. Also, acquisition of ESBL-producing Enterobacteriaceae during travel is associated with abdominal symptoms such as diarrhoea. Age also seemed to affect the risk of acquiring ESBL-producing Enterobacteriaceae, the highest risks were found among travellers ≥ 65 years.This thesis has contributed to increased understanding of the epidemiology of ESBL-producing Enterobacteriaceae and their susceptibility to both beta-lactam and non-beta-lactam agents.
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| 10. |
- Alvarsson, Jesper J.
(författare)
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Perspectives on wanted and unwanted sounds in outdoor environments : Studies of masking, stress recovery, and speech intelligibility
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- An acoustic environment contains sounds from various sound sources, some generally perceived as wanted, others as unwanted. This thesis examines the effects of wanted and unwanted sounds in acoustic environments, with regard to masking, stress recovery, and speech intelligibility.In urban settings, masking of unwanted sounds by sounds from water structures has been suggested as a way to improve the acoustic environment. However, Study I showed that the unwanted (road traffic) sound was better at masking the wanted (water) sound than vice versa, thus indicating that masking of unwanted sounds with sounds from water structures may prove difficult. Also, predictions by a partial loudness model of the auditory periphery overestimated the effect of masking, indicating that centrally located informational masking processes contribute to the effect. Some environments have also been shown to impair stress recovery; however studies using only auditory stimuli is lacking. Study II showed that a wanted (nature) sound improve stress recovery compared to unwanted (road traffic, ambient) sounds. This suggests that the acoustic environment influences stress recovery and that wanted sounds may facilitate stress recovery compared to unwanted sounds. An additional effect of unwanted sounds is impeded speech communication, commonly measured with speech intelligibility models. Study III showed that speech intelligibility starts to be negatively affected when the unwanted (aircraft sound) masker have equal or higher sound pressure level as the speech sound. Three models of speech intelligibility (speech intelligibility index, partial loudness and signal–to–noise ratio) predicted this effect well, with a slight disadvantage for the signal–to–noise ratio model. Together, Study I and III suggests that the partial loudness model is useful for determining effects of wanted and unwanted sounds in outdoor acoustic environments where variations in sound pressure level are large. But, in environments with large variations in other sound characteristics, models containing predictions of central processes would likely produce better results.The thesis concludes that wanted and unwanted characteristics of sounds in acoustic environments affect masking, stress recovery, and speech intelligibility, and that auditory perception models can predict these effects.
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| 11. |
- Andéhn, Mikael, 1982-
(författare)
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Place-of-Origin Effects on Brand Equity : Explicating the evaluative pertinence of product categories and association strength
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The country-of-origin effect - the alteration of judgment derived from an association to a place, is a much studied phenomenon with great potential implications for brand management and international marketing. However, in light of criticism towards the lack of conceptual development the extant literature, the relevance of the effect has been brought into question.Through an exploration of the psychology of the association between brands and places, the country-of-origin effect is reimagined focusing on the role of association strength as well as how the interplay between place and product categories can shape consumer attitudes.The results of a series of psychometric tests suggest that association strength and the interplay between place and product category constitute antecedent conditions that are crucial for determining if a country-of-origin effect will occur. These findings, and their implications for future research as well as for practice, suggest that a reevaluation of the country-of-origin effect with a widening of the scope to encompass the commercial relevance of place writ large is warranted.
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| 12. |
- Axelsson, Östen, 1971-
(författare)
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Aesthetic Appreciation Explicated
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present doctoral thesis outlines a new model in psychological aesthetics, named the Information-Load Model. This model asserts that aesthetic appreciation is grounded in the relationship between the amount of information of stimuli and people’s capacity to process this information. This relationship results in information load, which in turn creates emotional responses to stimuli. Aesthetic appreciation corresponds to an optimal degree of information load. Initially, the optimal degree is relatively low. As an individual learns to master information in a domain (e.g., photography), the degree of information load, which corresponds to aesthetic appreciation, increases. The present doctoral thesis is based on three empirical papers that explored what factors determine aesthetic appreciation of photographs and soundscapes. Experiment 1 of Paper I involved 34 psychology undergraduates and 564 photographs of various motifs. It resulted in a set of 189 adjectives related to the degree of aesthetic appreciation of photographs. The subsequent experiments employed attribute scales that were derived from this set of adjectives. In Experiment 2 of Paper I, 100 university students scaled 50 photographs on 141 attribute scales. Similarly, in Paper II, 100 university students scaled 50 soundscapes on 116 attribute scales. In Paper III, 10 psychology undergraduates and 5 photo professionals scaled 32 photographs on 27 attribute scales. To explore the underlying structure of the data sets, they were subjected to Multidimensional Scaling and Principal Components Analyses. Four general components, related to aesthetic appreciation, were found: Familiarity, Hedonic Tone, Expressiveness, and Uncertainty. These components result from the higher-order latent factor Information Load that underlies aesthetic appreciation.
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| 13. |
- Berglund, Mats, 1970-
(författare)
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Massans röst : Upplopp och gatubråk i Stockholm 1719–1848
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The thesis examines riots and street violence in Stockholm between 1719 and 1848. By studying open conflicts, the thesis explores changes in societal power structures which otherwise are hidden. The study shows how these levels of power and conflict structures interacted with one another and thereby contributed to the social development during the period; from a patriarchal society of privilege to a society based on a democratic view of the world. The thesis focuses on three collective actors; the people, the authorities and the press.The investigation of the people in the crowds shows that the military element, as well as the lower strata of labourers and servants, was significant in the early events. However, in later phases, middle class groupings such as burghers and civil servants, dominated the masses. These changes in the social composition of the crowds are tightly connected to a similar change in the aims of the riots; from local issues to national policy matters.Tactics of the authorities in their encounter with street disturbances also changed during the period, from passive observation by the police in the 18th century to an active military confrontational approach in the 19th century. The legal base was however strong throughout the period. The parties attached great importance to court proceedings, and knowledge of the legal system was surprisingly good among the common people.During the second half of the period, the press became firmly established. At the turn of the century 1800, there were two short glimpses of free press in connection to the political turbulence in 1792 and 1809. But it was mainly from the 1830's that the newspaper editors became significant actors in the riots. The popular demands for international news and politics gradually grew stronger during the period. A bottom-up perspective thus shows that popular political involvement in a significant way helped to pave the way for the coming breakthrough of democracy.
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| 14. |
- Cornell Kärnekull, Stina, 1985-
(författare)
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Auditory and Olfactory Abilities in Blind and Sighted Individuals : More Similarities than Differences
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Blind individuals face various challenges in everyday life because of the lack of visual input. However, since they need to rely on the non-visual senses for everyday tasks, for instance, when navigating the environment, the question has been raised as to whether perceptual and cognitive abilities in these senses may be enhanced. This question has mainly been addressed for auditory and tactile abilities, whereas there is considerably less research into the chemical senses, such as olfaction. However, to determine whether blindness has general effects, different senses and types of tasks should be studied, preferably in one and the same study. Therefore, throughout this thesis, analogous auditory and olfactory tasks that varied in cognitive complexity were studied. In Study I, absolute thresholds, discrimination, identification, episodic recognition (i.e., after a short retention interval), metacognition, and self-reported imagery ability were assessed in early blind, late blind, and sighted participants. The only objective measure on which the blind and sighted clearly differed was the auditory episodic recognition task. The fact that early blind but not late blind participants displayed better memory than the sighted suggested that the onset age of blindness may be important for whether this ability becomes enhanced following blindness. Furthermore, the early blind participants rated their auditory imagery ability higher than the sighted, whereas both early and late blind participants rated their olfactory imagery ability higher than the sighted. In Study II, the participants from Study I were followed up after more than a year and retested on auditory and olfactory episodic recognition and identification. This time, the early blind displayed no advantage over the sighted, suggesting that the influence of blindness on auditory memory may be modulated by the length of the retention interval. Moreover, in line with Study I, identification of sounds and odors was similar in the three groups. In Study III, early blind and sighted participants were examined for potential differences in autobiographical memory as evoked by sounds and odors, respectively. Blindness did not influence the reminiscence bumps (i.e., memory peaks in certain age intervals) or have any clear impact on the number of retrieved sound- or odor-evoked memories. Taken together, the present findings indicate that blindness has no general influence across tasks or sensory modalities. Rather, specific auditory abilities, such as episodic memory, may be enhanced in blind individuals, although such effects may depend on both the onset age of blindness and the length of the retention interval. In conclusion, for most perceptual and cognitive abilities examined, performance seemed unaffected by blindness.
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| 15. |
- Dahlberg, Karuna, 1979-
(författare)
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e-Assessed follow-up of postoperative recovery : developement, evaluation and patient experiences
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The majority of all surgeries are performed as day surgery. After discharge, patients are expected to take responsibility for their postoperative recovery themselves. Recovery Assessment by Phone Points (RAPP) is an e-assessment developed for assessing and providing follow-up on postoperative recovery, which includes the Swedish web-version of the Quality of Recovery questionnaire (SwQoR). It also enables the patient to get in contact with the day surgery unit. The overall aim of this thesis was to further develop and evaluate a systematic follow-up of postoperative recovery using a mobile app in adult persons undergoing day surgery, as well as to describe their experiences of postoperative recovery when using the mobile app. Study I: This study included three steps. Equivalence testing between the paper and app versions of the SwQoR showed agreement (n=69). The feasibility and acceptability evaluation showed that participants (n=63) were positive towards using a mobile phone application during postoperative recovery. Content validity of the SwQoR reduced the original 31 items to 24. Studies II and III: A multicentre, two-group, parallel, single-blind randomized controlled trial including 997 participants was conducted to investigate the effect of e-assessment on postoperative recovery (II) and cost-effectiveness (III) in a RAPP group compared with a control group. The RAPP group reported significantly better quality of postoperative recovery on postoperative days 7 and 14 compared with the control group. Moreover, RAPP may be cost-effective as it provides low-cost care. Study IV: Explored experience of postoperative recovery in participants using a mobile phone app during their postoperative recovery. Qualitative inductive semi-structured interviews (n=18) were performed. Findings showed that feeling safe is important during postoperative recovery. This feeling can be created by patients themselves, but sufficient support and information from health care and next of kin is needed. Overall, this thesis showed positive results for RAPP, suggesting that RAPP is a solution that may benefit patients after day surgery.
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| 16. |
- Eklund, Rasmus, 1989-
(författare)
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Electrophysiological correlates of consciousness
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- How does the brain enable us to experience seeing or hearing a stimulus? If a stimulus is repeatedly presented at the awareness threshold, subjects will report that they are aware of the stimulus on half of the presentations. Electroencephalography (EEG) can be used to non-invasively record neural activity as event-related potentials (ERPs). The contrastive analysis of neural activity to trials rated as aware minus neural activity to trials rated as unaware reveals the neural correlates of consciousness (NCC). Research on the NCC in vision has resulted in two ERPs: an early negative difference wave (visual awareness negativity, VAN) and a subsequent late positivity (LP). Visual awareness may be reflected by one or both of these ERPs. However, the contrastive analysis (aware minus unaware) may not isolate the NCC because it arguably compares aware processing with a combination of unaware processing and no processing. In support, previous research that tried to isolate a comparison between aware processing and unaware processing found that LP was the only NCC. However, subsequent replications suggested VAN and LP as NCC. Because of these mixed results, we followed up on these studies in Study I with a preregistered design that manipulated stimulus size. Results showed VAN and LP as NCC. The findings provide evidence for VAN as an early NCC.Another main goal of this thesis was to investigate auditory awareness. In Study II, an auditory threshold task was used, and the contrastive analysis revealed an early negative difference wave (auditory awareness negativity, AAN) and LP. These ERPs are comparable to VAN and LP in vision. Because post-perceptual processes related to responding may confound the NCC in contrastive analysis, no-response tasks can be used to isolate awareness-related activity. In vision, a previous study in which the manual response requirement was manipulated showed effects on LP but not on VAN. In Study III, we used a similar task with auditory stimuli at the awareness threshold. Results suggested that AAN and LP are unaffected by the response manipulation. However, the present no-response task may not be optimal for removing post-perceptual processing because subjects need to reflect on their experience even if they do not need to respond manually. Additional analyses that attempted source localization of the AAN suggested that it is generated in auditory cortex.From a theoretical perspective, one view of these results is that VAN and AAN reflect local recurrent processing and that this is the neural signature of awareness, whereas LP reflects global recurrent processing that enables reporting. Other views suggest that VAN and AAN merely reflect preconscious processes, whereas LP and global recurrent processing reflect consciousness. The studies described in this thesis do not support one theory over the other but provide robust evidence for early neural correlates of visual and auditory awareness.
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| 17. |
- Grundberg, Ida, 1982-
(författare)
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Genotyping and Mutation Detection In Situ : Development and application of single-molecule techniques
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human body is composed of trillions of cells closely working together to maintain a functional organism. Every cell is unique in molecular composition and can acquire genetic variations that might cause it to turn pathological. It is essential to develop improved tools to better understand the development of normal and disease tissue, ideally enabling single-cell expression studies in preserved context of complex tissue with single-nucleotide resolution. This thesis presents the development and application of a new in situ method for localized detection and genotyping of individual transcripts directly in cells and tissues. The described technique utilizes padlock probes and target-primed rolling circle amplification and is highly suitable for sensitive in situ analysis. First, a new strategy for directed cleavage of single stranded DNA was investigated, e.g. nucleic acid targets with extended 3´ ends, for successful initiation of rolling circle amplification. The presented cleavage strategy is simple and applicable for subsequent enzymatic reactions, e.g. ligation and polymerization. Specific cleavage of long target overhangs was demonstrated in synthetic oligonucleotides and in genomic DNA and the detection efficiency was substantially increased. For multiplex detection and genotyping of individual transcripts in single cells, a new in situ method was developed. The technique showed a satisfactorily detection efficiency and was later applied as a general mutation analysis tool for detection of KRAS point mutations in complex tumor tissue sections, e.g. formalin-fixed, paraffin-embedded tumor tissues and cytologic tumor imprints. Mutation status was assessed in patient samples by in situ padlock probe detection and results were confirmed by DNA-sequencing. Finally, the method was adapted for simultaneous detection of individual mRNA molecules and endogenous protein modifications in single cells using padlock probes and in situ PLA. This assay will be useful for gene expression analysis and exploration of new drugs with vague effector sites. To our knowledge, no other technique exists today that offers in situ transcript detection with single-nucleotide resolution in heterogeneous tissues. The method will especially be suitable for discrimination of highly similar transcripts, e.g. splice variants, SNPs and point mutations, within gene expression studies and for cancer diagnostics.
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| 18. |
- Ivanenko, Yevhen
(författare)
-
Optimization and Physical Bounds for Passive and Non-passive Systems
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Physical bounds in electromagnetic field theory have been of interest for more than a decade. Considering electromagnetic structures from the system theory perspective, as systems satisfying linearity, time-invariance, causality and passivity, it is possible to characterize their transfer functions via Herglotz functions. Herglotz functions are useful in modeling of passive systems with applications in mathematical physics, engineering, and modeling of wave phenomena in materials and scattering. Physical bounds on passive systems can be derived in the form of sum rules, which are based on low- and high-frequency asymptotics of the corresponding Herglotz functions. These bounds provide an insight into factors limiting the performance of a given system, as well as the knowledge about possibilities to improve a desired system from a design point of view. However, the asymptotics of the Herglotz functions do not always exist for a given system, and thus a new method for determination of physical bounds is required. In Papers I–II of this thesis, a rigorous mathematical framework for a convex optimization approach based on general weighted Lp-norms, 1≤p≤∞, is introduced. The developed framework is used to approximate a desired system response, and to determine an optimal performance in realization of a system satisfying the target requirement. The approximation is carried out using Herglotz functions, B-splines, and convex optimization. Papers III–IV of this thesis concern modeling and determination of optimal performance bounds for causal, but not passive systems. To model them, a new class of functions, the quasi-Herglotz functions, is introduced. The new functions are defined as differences of two Herglotz functions and preserve the majority of the properties of Herglotz functions useful for the mathematical framework based on convex optimization. We consider modeling of gain media with desired properties as a causal system, which can be active over certain frequencies or frequency intervals. Here, sum rules can also be used under certain assumptions.In Papers V–VII of this thesis, the optical theorem for scatterers immersed in lossy media is revisited. Two versions of the optical theorem are derived: one based on internal equivalent currents and the other based on external fields in terms of a T-matrix formalism, respectively. The theorems are exploited to derive fundamental bounds on absorption by using elementary optimization techniques. The theory has a potential impact in applications where the surrounding losses cannot be neglected, e.g., in medicine, plasmonic photothermal therapy, radio frequency absorption of gold nanoparticle suspensions, etc. In addition to this, a new method for detection of electrophoretic resonances in a material with Drude-type of dispersion, which is placed in a straight waveguide, is proposed.
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| 19. |
- Javadi, Mohammad Saleh, 1986-
(författare)
-
Computer Vision Algorithms for Intelligent Transportation Systems Applications
- 2018
-
Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent years, Intelligent Transportation Systems (ITS) have emerged asan efficient way of enhancing traffic flow, safety and management. Thesegoals are realized by combining various technologies and analyzing the acquireddata from vehicles and roadways. Among all ITS technologies, computervision solutions have the advantages of high flexibility, easy maintenanceand high price-performance ratio that make them very popular fortransportation surveillance systems. However, computer vision solutionsare demanding and challenging due to computational complexity, reliability,efficiency and accuracy among other aspects. In this thesis, three transportation surveillance systems based on computervision are presented. These systems are able to interpret the imagedata and extract the information about the presence, speed and class ofvehicles, respectively. The image data in these proposed systems are acquiredusing Unmanned Aerial Vehicle (UAV) as a non-stationary sourceand roadside camera as a stationary source. The goal of these works is toenhance the general performance of accuracy and robustness of the systemswith variant illumination and traffic conditions. This is a compilation thesis in systems engineering consisting of threeparts. The red thread through each part is a transportation surveillancesystem. The first part presents a change detection system using aerial imagesof a cargo port. The extracted information shows how the space isutilized at various times aiming for further management and developmentof the port. The proposed solution can be used at different viewpoints andillumination levels e.g. at sunset. The method is able to transform the imagestaken from different viewpoints and match them together. Thereafter,it detects discrepancies between the images using a proposed adaptive localthreshold. In the second part, a video-based vehicle's speed estimationsystem is presented. The measured speeds are essential information for lawenforcement and they also provide an estimation of traffic flow at certainpoints on the road. The system employs several intrusion lines to extractthe movement pattern of each vehicle (non-equidistant sampling) as an inputfeature to the proposed analytical model. In addition, other parameters such as camera sampling rate and distances between intrusion lines are alsotaken into account to address the uncertainty in the measurements and toobtain the probability density function of the vehicle's speed. In the thirdpart, a vehicle classification system is provided to categorize vehicles into\private car", \light trailer", \lorry or bus" and \heavy trailer". This informationcan be used by authorities for surveillance and development ofthe roads. The proposed system consists of multiple fuzzy c-means clusterings using input features of length, width and speed of each vehicle. Thesystem has been constructed by using prior knowledge of traffic regulationsregarding each class of vehicle in order to enhance the classification performance.
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| 20. |
- Kühnemund, Malte
(författare)
-
Single Molecule Detection : Microfluidic Automation and Digital Quantification
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Much of recent progress in medical research and diagnostics has been enabled through the advances in molecular analysis technologies, which now permit the detection and analysis of single molecules with high sensitivity and specificity. Assay sensitivity is fundamentally limited by the efficiency of the detection method used for read-out. Inefficient detection systems are usually compensated for by molecular amplification at the cost of elevated assay complexity.This thesis presents microfluidic automation and digital quantification of targeted nucleic acid detection methods based on padlock and selector probes and rolling circle amplification (RCA). In paper I, the highly sensitive, yet complex circle-to-circle amplification assay was automated on a digital microfluidic chip. In paper II, a new RCA product (RCP) sensing principle was developed based on resistive pulse sensing that allows label free digital RCP quantification. In paper III, a microfluidic chip for spatial RCP enrichment was developed, which enables the detection of RCPs with an unprecedented efficiency and allows for deeper analysis of enriched RCPs through next generation sequencing chemistry. In paper IV, a smart phone was converted into a multiplex fluorescent imaging device that enables imaging and quantification of RCPs on slides as well as within cells and tissues. KRAS point mutations were detected (i) in situ, directly in tumor tissue, and (ii) by targeted sequencing of extracted tumor DNA, imaged with the smart phone RCP imager. This thesis describes the building blocks required for the development of highly sensitive low-cost RCA-based nucleic acid analysis devices for utilization in research and diagnostics.
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| 21. |
- Lee, Hower Hao Zhe, 1994-
(författare)
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Next Generation targeted In Situ Sequencing (NGISS) : New wave molecular tools for targeted sequence capture
- 2024
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Spatially resolved transcriptomics (SRT) approaches have allowed for the investigation of transcriptomic defined cellular diversity of biological tissues previously unseen. A multitude of different SRT technologies have been developed over the years, addressing the various needs of the scientific community by enabling the characterization of molecular signatures in situ, while preserving tissue morphology.Despite the multitude of SRT techniques developed, there is still no single ‘best’ SRT approach, due to trade offs different techniques have to compromise on. The SRT quadrilemma, termed in my thesis – Throughput, Specificity, Sensitivity and Multiplexing are the main characteristics that the dream SRT should possess, but is theoretically impossible due to the mutually exclusive nature of these characteristics. The work in this thesis focuses on the development of In Situ Sequencing (ISS) with padlock probes and rolling circle amplification, tackling the SRT quadrilemma.In paper I, we investigate the efficiency bottlenecks of cDNA-HybISS against a commercial kit that targets RNA directly, circumventing cDNA synthesis in situ. We found that by circumventing cDNA synthesis in situ, we are able to improve the detection efficiency 5 fold. In addition, the increase in sensitivity enhanced analytical capability of our data and allowed for low, 5X magnification imaging.In Paper II, we provide an end to end in situ transcriptomic solution with a RNA targeting ISS chemistry with improved detection efficiency compared to cDNA-HybISS and user friendly and well documented computational tools for probe design, image registration, decoding and analysis. In addition, we also demonstrate that our RNA-ISS is compatible with posterior stainings such as multiplexed antibody staining, opening up the possibility of spatial multi-omics all while maintaining cost effectiveness, customizability and ease of implementation of RNA-ISS.In paper III, we show that we are able to achieve single nucleotide specificity with RNA targeted ISS. We show that we are able to distinguish human and mouse cells from the genotyping experiment with competing padlock probes targeting a conserved region of human and mouse beta-actin sequence that differs by a single base. In addition to the improved detection efficiency we show that the specificity with single nucleotide RNA-ISS is comparable to the established cDNA-BaSSIS method.In paper IV, we further developed a RNA gap filling approach for genotyping. Here, we leveraged on a polymerase mediated approach for sequence capture, reverse transcribing a stretch of unknown sequences on RNA into the probe before ligation, amplification and sequencing readout. We demonstrate that we are able to fill a gap of 20nt with high fidelity as a first proof of concept experiment.Lastly, in paper V, we employed targeted cDNA-HybISS for a proof of concept study as a high throughput molecular screening tool for a cohort study of control and schizophrenic post mortem study of the prefrontal cortex. We attempt to map cell type compositions and macroscopic tissue organization within this cohort as an exploratory study.The work in this thesis presents the development of next generation in situ sequencing with improved sensitivity, specificity, throughput and multiplexing as a next generation molecular tool for spatial mapping of molecular signatures within biological samples in health and disease.
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| 22. |
- Mathot, Lucy, 1986-
(författare)
-
From Tissue to Mutations : Genetic Profiling of Colorectal Cancer
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Comprehensive characterisation of the mutational landscapes of solid tumours is a multistep process involving the collection of suitable samples, the extraction of nucleic acids and the preparation of these materials for mutational analyses. In this thesis, I aimed to develop a streamlined process for the analysis of colorectal cancer (CRC) patient samples in order to identify novel mutations that hallmark the development of advanced disease.Papers I and II outline a technique for serial extraction of nucleic acids from frozen tissue that we developed and subsequently implemented on a robotic platform to enable high-throughput processing. The extracted nucleic acids were validated in downstream processes relevant for genetic analyses, including traditional Sanger and next generation sequencing techniques.In Paper III, we developed a genotyping method based on multiplex ligation-dependent genome amplification. The method was designed such that InDel polymorphisms of between 30 and 70 % prevalence in a European population were selected and amplified in a multiplex PCR assay. DNA from 24 patient-matched colorectal tumour and normal tissues was genotyped and paired with a high match probability.In Paper IV, we performed targeted resequencing of 107 primary CRCs, of which approximately half developed metastatic disease or had distant metastases at the time of diagnosis. We chose to analyse 676 genes based on their involvement in key signalling pathways in CRC. We found an enrichment of mutations in the Eph receptor tyrosine kinase gene family in metastatic patients, indicating a potential role for these genes in CRC metastasis.This thesis outlines a series of procedures that can be employed in a high-throughput setting for the analysis of solid tumours. We applied these methods to the analysis of colorectal tumours and propose a link between novel somatic mutations and metastatic disease.
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| 23. |
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| 24. |
- Nilsson, Kristina, 1976-
(författare)
-
Hybrid Methods for Coreference Resolution in Swedish
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis is to improve coreference resolution in Swedish by providing a hybrid approach based on combining data-driven methods and linguistic knowledge. Coreference resolution here consists in identifying all expressions in a text that have the same referent, for example, a person or an object. The linguistic knowledge is based on Accessibility Theory (Ariel 1990). This is used for guiding the selection of likely anaphor-antecedent pairs from the set of all possible such pairs in a text. The data-driven method adopted is Memory-Based Learning (MBL), a supervised method based on the idea that learning means storing experiences in memory, and that new problems are solved by reusing solutions from similar experiences (Daelemans and Van den Bosch 2005). The referring expressions covered by the system are names, definite descriptions, and pronouns. In order to maximize performance, we use different classifiers with a specific set of linguistically motivated features for each type of expression. The great majority of features used for classification are domain- and language-independent. We demonstrate two ways of using this method of linguistically motivated selection of anaphor-antecedent pairs. First, the amount of training examples stored in memory is reduced. We find that for coreference resolution of definite descriptions and names, the amount of training data can thereby be reduced with only a minor loss in performance, but for pronoun resolution there is a negative effect. Second, selection can be used for improving on coreference resolution results. This is the first step in our hybrid approach to coreference resolution, where the second step is the application of an MBL classifier for determining coreference between the selected pairs. Results indicate that this hybrid approach is advantageous for coreference resolution of definite descriptions and names. For pronoun resolution, there is a negative effect on recall along with a positive effect on precision.
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| 25. |
- Nilsson, Sara, 1990-
(författare)
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How requirements development could support design of effective and resource-efficient offerings
- 2017
-
Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- What a company offers its customers has to fulfil several different needs, desires, constraints, which can originate from multiple different sources that affect the offering throughout its life cycle. All these criteria have to come together and be translated into statements that can support the designer’s understanding of the offering’s purpose. This translation is done through a requirements development process to provide a controlled process to define statements that describe what the offering is supposed to fulfil.This research provides insights on key challenges and success factors in requirements development to support the design of effective and resource-efficient offerings. Namely, it identifies crucial sources and aspects to be considered, and a requirements development process demonstrating how to overcome identified challenges. By getting the requirements right from the beginning, sub-optimisation and unnecessary time and risks can be avoided. The consideration of accurate sources and aspects is considered to be one of the most important factors for the successful design of offerings. It is also in the earliest phases of design, that is to say requirements development, where one has the greatest possibility to affect the environmental impact of the offering. What is missing, however, is sufficient and appropriate support in industry on how to do so.The gap between the three areas of effectiveness and resource efficiency, design of integrated offerings, and requirements development has been investigated. Results are based on findings in the literature and in industry, identified primarily by qualitative studies. In the research, 15 different companies have been included through a number of interviews and discussions.Key sources and aspects to consider in the requirements development process are identified along with challenges, and success factors that can be utilised to overcome the identified challenges. This research’s final results include an adapted requirements development process that considers the earlier-mentioned sources and aspect, challenges, and success factors. Such a requirements development process should support the design of effective and resource-efficient offerings.
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| 26. |
- Partel, Gabriele, 1988-
(författare)
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Image and Data Analysis for Spatially Resolved Transcriptomics : Decrypting fine-scale spatial heterogeneity of tissue's molecular architecture
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Our understanding of the biological complexity in multicellular organisms has progressed at tremendous pace in the last century and even more in the last decades with the advent of sequencing technologies that make it possible to interrogate the genome and transcriptome of individual cells. It is now possible to even spatially profile the transcriptomic landscape of tissue architectures to study the molecular organization of tissue heterogeneity at subcellular resolution. Newly developed spatially resolved transcriptomic techniques are producing large amounts of high-dimensional image data with increasing throughput, that need to be processed and analysed for extracting biological relevant information that has the potential to lead to new knowledge and discoveries. The work included in this thesis aims to provide image and data analysis tools for serving this new developing field of spatially resolved transcriptomics to fulfill its purpose. First, an image analysis workflow is presented for processing and analysing images acquired with in situ sequencing protocols, aiming to extract and decode molecular features that map the spatial transcriptomic landscape in tissue sections. This thesis also presents computational methods to explore and analyse the decoded spatial gene expression for studying the spatial molecular heterogeneity of tissue architectures at different scales. In one case, it is demonstrated how dimensionality reduction and clustering of the decoded gene expression spatial profiles can be exploited and used to identify reproducible spatial compartments corresponding to know anatomical regions across mouse brain sections from different individuals. And lastly, this thesis presents an unsupervised computational method that leverages advanced deep learning techniques on graphs to model the spatial gene expression at cellular and subcellular resolution. It provides a low dimensional representation of spatial organization and interaction, finding functional units that in many cases correspond to different cell types in the local tissue environment, without the need for cell segmentation.
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| 27. |
- Qian, Xiaoyan, 1989-
(författare)
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Towards comprehensive cellular atlases : High-throughput cell mapping by in situ sequencing
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- With recent technological advancements in single-cell biology, many aspects of individual cells are characterized with unprecedented resolution and details. Cell types in human and model organisms are redefined, and multiple organ-wide atlases are proposed to integrate different types of data to provide a comprehensive view of biological systems at cellular resolution. Incorporating location information of cells in such atlases is crucial to understanding the structure and functions. Several spatially resolved transcriptomics technologies may serve this purpose, and in situ sequencing (ISS) is among the most powerful ones.ISS detects the expression of tens to hundreds of genes in situ, i.e. inside preserved cells and tissues. ISS is a targeted approach, using probes designed to identify specific transcripts. Its key advantages, as compared to other spatially resolved gene expression analysis methods, are high throughput, cellular resolution and tissue compatibility, making it a tool ideally suited for spatial cell mapping. The work included in this thesis aims to develop tools and methods for this application.In paper I, a network analysis tool was developed to analyze ISS and other spatially resolved data. The tool enables smooth visualization of large datasets and generates networks based on colocalization. It also includes functions to test statistical significance and resolve tissue heterogeneity.In paper II, we studied spatio-temporal patterns of immune response in tuberculosis granuloma by targeting immune markers with ISS. Using the tool developed in paper I together with other methods, we established an immune response time course at the granuloma sites and found histologically different granulomas based on transcriptional information. The paper demonstrated that ISS can robustly detect transcripts in formalin-fixed paraffin-embedded tissues across biological samples and reveal biologically relevant structures.In paper III, we developed probabilistic cell typing by in situ sequencing (pciSeq), a method to spatially map cell types defined by single-cell RNA-sequencing. pciSeq is an integrated pipeline that includes gene selection, image analysis, barcode calling and cell type calling. We mapped closely related interneuron cell types of the mouse hippocampal CA1 region in 14 coronal sections and validated the results against ground truth.In paper IV, we investigated the quantification bias of ISS resulting from the probe target selection. We developed a method to sequence in situ synthesized cDNA and found that the read coverage of in situ cDNA library reflected ISS counts more closely than conventional RNA sequencing, making it possible, to some extent, to predict a probe’s performance and guide the probe design.Taken together, the developments described in this thesis comprise several tools that make ISS suitable for building cellular atlases via large-scale spatial mapping.
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| 28. |
- Unander, Tomas
(författare)
-
Characterization of Low Cost Printed Sensors for Smart Packaging
- 2008
-
Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Currently there are very significant interests in printed electronics in the world. The possibility to produce electronics in a roll to roll printing process will considerably reduce the cost of the electronic devices. However, these new devices will most probably not replace the traditional silicon based electronics, but will be a complement in low cost applications such as in intelligent packages and other printable media. One interesting area is printable low cost sensors that add value to packages. In this thesis a study of the performance of low cost sensors is presented. The sensors were fabricated using commercial printing processes used in the graphical printing business. The sensors were characterized and evaluated for the intended application. The evaluated sensors were moisture sensing sensor solutions and touch sensitive sensor solutions. A printable touch sensitive sensor solution is presented where the sensor is incorporated into a high quality image such as in point of sales displays. The sensor solution showed good touch sensitivity at a variety of humidity levels. Four printed moisture sensor concepts are presented and characterized. Firstly, a moisture sensor that shows good correlation to the moisture content of cellulose based substrates. Secondly, a sensor that measures the relative humidity in the air, the sensor has a measuring accuracy of 0.22% at high relative humidity levels. Thirdly, a moisture sensor that utilizes unsintered silver nano-particles to measure the relative humidity in the air, the sensor has a linear response at very low relative humidity levels. And fourth, an action activated energy cell that provides power when activated by moisture. A concept of remote moisture sensing that utilizes ordinary low cost RFID tags has also been presented and characterized. The remote sensor solution works both with passive and semi-passive RFID systems. The study shows that it is possible to manufacture low cost sensors in commercial printing processes.
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| 29. |
- Wiger, Malin, 1980-
(författare)
-
Logistics management operationalised in a healthcare context : Understanding care chain effectiveness through logistics management theories and systems theory
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Healthcare improvements is constantly relevant and an important topic. Healthcare is frequently being called upon to be more cost-efficient and still fulfil demands regarding waiting times, quality and availability. Experience from structural changes in other contexts gives reason to be positive about the potential for logistics improvements in the healthcare sector as well. From a logistics perspective patients pass different care functions, units, organisations and health facilities. It is assumed that logistics management knowledge applied in healthcare can lead to lower costs, shorter waiting times, better patient service, shorter treatment times and increased capacity. This dissertation therefore presents an exploration of how logistics management theories can be operationalised in a healthcare context to understand care chain effectiveness.Theoretically, the operationalisation is done by systems theory creating compatibility between logistics management theories and the healthcare context. As a first step, features for a logistics system forms features for achieving care chain effectiveness. High care chain effectiveness is thus a desired condition and the care delivery system is the tool to achieve it. As the final step in the operationalisation the features for care chain effectiveness are in turn used to analyse today’s practices. Empirically, the research is based on qualitative data from a single case study with multiple units of analysis. It includes four care units at one of Sweden’s university hospitals, where the data is gathered through interviews, insight into management systems and document analysis. One of the main results is the 21 areas identified for analysing today’s practices by means of features for care chain effectiveness. Another main result is the four important concepts revealed through the operationalisation:Lead time - the episode of care from order to delivery as the amount of time for patient cases between first contact with healthcare and the last.Patient order fulfilment - fulfilment of patients’ needs, broken down into several smaller steps performed over time within different care units in one or several organisations, consisting of five sub-processes - order handling, diagnosis, treatment, follow-up, and discharge.True demand – patients’ needs that is to be met and thus sets what care to deliver, i.e. the production plan and the subordinate resource plan.System boundaries - defines which care units to include when focusing on the care delivery system’s performance as a whole and should be more important than the performance and productivity of each individual care unit.A number of direct suggestions for care chain improvement can also be found in the concluding remarks, for example that objectives linked to economic influx or penalty narrow the system and that lead time data on an aggregated level is needed to cover episodes of care. The theoretical contribution of the dissertation is to the field of logistics management through the methodological development of using these theories in a new context. The managerial contribution is to healthcare managers through providing opportunities to improve care chains primarily by means of a greater understanding of care delivery systems.
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| 30. |
- Zajac, Pawel, 1982-
(författare)
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Parallel target selection by trinucleotide threading
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- DNA is the code for all life. Via intermediary RNA the information encoded by the genome is relayed to proteins executing the various functions in a cell. Together, this repertoire of inherently linked biological macromolecules determines all characteristics and features of a cell. Technological advancements during the last decades have enabled the pursuit of novel types of studies and the investigation of the cell and its constituents at a progressively higher level of detail. This has shed light on numerous cellular processes and on the underpinnings of several diseases. For the majority of studies focusing on nucleic acids, an amplification step has to be implemented before an analysis, scoring or interrogation method translates the amplified material into relevant biological information. This information can, for instance, be the genotype of particular SNPs or STRs, or the abundance level of a set of interesting transcripts. As such, amplification plays a significant role in nucleic acid assays. Over the years, a number of techniques – most notably PCR – has been devised to meet this amplification need, specifically or randomly multiplying desired regions. However, many of the approaches do not scale up easily rendering comprehensive studies cumbersome, time-consuming and necessitating large quantities of material.Trinucleotide threading (TnT) – forming the red thread throughout this thesis – is a multiplex amplification method, enabling simultaneous targeted amplification of several nucleic acid regions in a specific manner. TnT begins with a controlled linear DNA thread formation, each type of thread corresponding to a segment of interest, by a gap-fill reaction using a restricted trinucleotide set. The whole collection of created threads is subsequently subjected to an exponential PCR amplification employing a single primer pair. The generated material can thereafter be analyzed with a multitude of readout and detection platforms depending on the issue or characteristic under consideration.TnT offers a high level of specificity by harnessing the inherent specificities of a polymerase and a ligase acting on a nucleotide set encompassing three out of the four nucleotide types. Accordingly, several erroneous events have to occur in order to produce artifacts. This necessitates override of a number of control points.The studies constituting this thesis demonstrate integration of the TnT amplification strategy in assays for analysis of various aspects of DNA and RNA. TnT was adapted for expression profiling of intermediately-sized gene sets using both conventional DNA microarrays and massively parallel second generation 454 sequencing for readout. TnT, in conjunction with 454 sequencing, was also employed for allelotyping, defined as determination of allele frequencies in a cohort. In this study, 147 SNPs were simultaneously assayed in a pool comprising genomic DNA of 462 individuals. Finally, TnT was recruited for parallel amplification of STR loci with detection relying on capillary gel electrophoresis. In all investigations, the material generated with TnT was of sufficient quality and quantity to produce reliable and accurate biological information.Taken together, TnT represents a viable multiplex amplification technique permitting parallel amplification of genomic segments, for instance harboring polymorphisms, or of expressed genes. In addition to these, this versatile amplification module can be implemented in assays targeting a range of other features of genomes and transcriptomes.
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| 31. |
- Ahlford, Annika, 1980-
(författare)
-
Applications of Four-Colour Fluorescent Primer Extension Technology for SNP Analysis and Discovery
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Studies on genetic variation can reveal effects on traits and disease, both in humans and in model organisms. Good technology for the analysis of DNA sequence variations is critical. Currently the development towards assays for large-scale and parallel DNA sequencing and genotyping is progressing rapidly. Single base primer extension (SBE) is a robust reaction principle based on four-colour fluorescent terminating nucleotides to interrogate all four DNA nucleotides in a single reaction. In this thesis, SBE methods were applied to the analysis and discovery of single nucleotide polymorphism (SNP) in the model organism Drosophila melanogaster and in humans. The tag-array minisequencing system in a microarray format is convenient for intermediate sized genotyping projects. The system is scalable and flexible to adapt to specialized and novel applications. In Study I of the thesis a tool was established to automate quality control of clustered genotype data. By calculating “Silhouette scores”, the SNP genotype assignment can be evaluated by a single numeric measure. Silhouette scores were then applied in Study I to compare the performance of four DNA polymerases and in Study III to evaluate freeze-dried reagents in the tag-array minisequencing system. The characteristics of the tag-array minisequencing system makes it suitable for inexpensive genome-wide gene mapping in the fruit fly. In Study II a high-resolution SNP map, and 293 genotyping assays, were established across the X, 2nd and 3rd chromosomes to distinguish commonly used Drosophila strains. A database of the SNP markers and a program for automatic allele calling and identification of map positions of mutants was also developed. The utility of the system was demonstrated by rapid mapping of 14 genes that disrupt embryonic muscle patterning. In Study III the tag-array minisequencing system was adapted to a lab-on-a-chip format for diagnostic testing for mutations in the TP53 gene. Freeze-drying was evaluated for storing reagents, including thermo-sensitive enzymes, on the microchip to reduce the complexity of the integrated test. Correct genotyping results were obtained using freeze-dried reagents in each reaction step of the genotyping protocol, both in test tubes and in single polymer test chambers. The results showed the potential of the approach to be implemented in fully integrated systems. The four-colour chemistry of SBE has been developed further to allow massively parallel sequencing (MPS) of short DNA fragments as in the Genome Analyzer system (Solexa/Illumina). In Study IV MPS was used to compare Nimblegen arrays and the SureSelect solution-based system for targeted enrichment of 56 continuous human candidate-gene regions totalling 3.1 Mb in size. Both methods detected known SNPs and discovered novel SNPs in the target regions, demonstrating the feasibility for complexity reduction of sequencing libraries by hybridization methods.
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| 32. |
- Ardabili, Sahar, 1982-
(författare)
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Microfluidic bases sample preparation for blood stream infections
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Microfluidics promises to re-shape the current health-care system by transferring diagnostic tools from central laboratories to close vicinity of the patient (point-of-care). One of the most important operational steps in any diagnostic platform is sample preparation, which is the main subject in this thesis. The goal of sample preparation is to isolate targets of interest from their surroundings. The work in this thesis is based on three ways to isolate bacteria: immune-based isolation, selective cell lysis, size-based separation.The first sample-preparation approach uses antibodies against lipopolysaccharides (LPS), which are surface molecules found on all gram-negative bacteria. There are two characteristics that make this surface molecule interesting. First, it is highly abundant: one bacterium has approximately a million LPS molecules on its cell-wall. Second, the molecule has a conserved region within all gram-negative bacteria, so using one affinity molecule to isolate disease-causing gram-negative bacteria is an attractive option, particularly from the point of view of sample preparation. The main challenge, however, is antigen accessibility. To address this, we have developed a treatment protocol that improves the capturing efficiency.The strategy behind selective cell lysis takes advantage of the differences between the blood-cell membrane and the bacterial cell-wall. These fundamental differences make it possible to lyse (destroy) blood-cells selectively while keeping the target of interest, here the bacteria, intact and, what is more important alive. Viability plays an important role in determining antibiotic susceptibility.Difference in size is another well-used characteristic for sample- separation. Inertial microfluidics can focus size-dependent particle at high flow-rates. Thus, particles of 10 µm diameter were positioned in precise streamlines within a curved channel. The focused particles can then be collected at defined outlets. This approach was then used to isolate white blood cells, which account for approximately 1% of the whole blood. In such a device particles of 2µm diameter (size of bacteria) would not be focused and thereby present at every outlet. To separate bacteria from blood elasto-inertial microfluidics was used. Here, e blood components are diverted to center of the channels while smaller bacteria remain in the side streams and can subsequently be separated.
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| 33. |
- Bergens, Oscar, 1991-
(författare)
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Chronic Systemic Inflammation, Body Composition and Physical Activity Behaviours in Older Adults
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ageing is associated with a gradual physical decline accompanied by changes in body composition. The occurrence of a low-grade yet chronic state of systemic inflammation has gained interest for its potential consequences in the ageing process. Importantly, a physically active lifestyle may promote the maintenance of muscle mass, reduction in adipose tissue, and alleviate progression of a chronic pro-inflammatory state. The overall aim of this thesis was to explore relationships between biomarkers of systemic inflammation, body composition, and physical activity behaviours in community-dwelling older adults aged 65 to 70 years.A main finding of the thesis is the existence of associations between body composition and systemic inflammation in older adults, where excess adipose tissue is adversely associated with levels of inflammatory biomarkers in older women. Inverse associations were also observed between muscle mass and levels of pro-inflammatory biomarkers in older women. This thesis also highlights sex-specific associations between systemic inflammation and physical activity behaviours. Longer time spent sedentary was also associated with higher levels of proinflammatory biomarkers in older women and lower level of antiinflammatory biomarkers in older men. Reallocating time spent in activities of lower intensities with higher intensities was associated with lower levels of pro-inflammatory biomarkers in older women. Overall, the findings of this thesis support efforts promoting physical activity at the expense of sedentary time in order to combat age-related systemic inflammation and metabolic risk in older adults.
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| 34. |
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| 35. |
- Govik, Alexander
(författare)
-
Finite Element Analysis of Sheet Metal Assemblies : Prediction of Product Performance Considering the Manufacturing Process
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis concerns the development of methodologies to be used to simulate complete manufacturing chains of sheet components and the study of how different mechanical properties propagate and influence succeeding component performance.Since sheet metal assemblies are a major constituent of a wide range of products it is vital to develop methodologies that enable detailed evaluation of assembly designs and manufacturing processes. The manufacturing process influences several key aspects of a sheet metal assembly, aspects such as shape fulfilment, variation and risk of material failure.Developments in computer-aided engineering and computational resources have made simulation-based process and product development efficient and useful since it allows for detailed, rapid evaluation of the capabilities and qualities of both process and product. Simulations of individual manufacturing processes are useful, but greater benefits can be gained by studying the complete sequence of a product's manufacturing processes. This enables evaluation of the entire manufacturing process chain, as well as the final product. Moreover, the accuracy of each individual manufacturing process simulation is improved by establishing appropriate initial conditions, including inherited material properties.In this thesis, a methodology of sequentially simulating each step in the manufacturing process of a sheet metal assembly is presented. The methodology is thoroughly studied using different application examples with experimental validation. The importance of information transfer between all simulation steps is also studied. Furthermore, the methodology is used as the foundation of a new approach to investigate the variation of mechanical properties in a sheet metal assembly. The multi-stage manufacturing process of the assembly is segmented, and stochastic analyses of each stage is performed and coupled to the succeeding stage in order to predict the assembly's final variation in properties.Two additional studies are presented where the methodology of chaining manufacturing processes is utilised. The influence of the dual phase microstructure on non-linear strain recovery is investigated using a micromechanical approach that considers the annealing process chain. It is vital to understand the non-linear strain recovery in order to improve springback prediction. In addition, the prediction of fracture in a dual phase steel subjected to non-linear straining is studied by simulating the manufacturing chain and subsequent stretch test of a sheet metal component.
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| 36. |
- Henriksson, Sara, 1979-
(författare)
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Application of Padlock Probe Based Nucleic Acid Analysis In Situ
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The great variation displayed by nucleic acid molecules in human cells, and the continuous discovery of their impact on life, consequently require continuous refinements of molecular analysis techniques. Padlock probes and rolling circle amplification offer single nucleotide discrimination in situ, a high signal-to-noise ratio and localized detection within cells and tissues. In this thesis, in situ detection of nucleic acids with padlock probes and rolling circle amplification was applied for detection of DNA in the single cell gel electrophoresis assay to detect nuclear and mitochondrial DNA. This assay is used to measure DNA damage and repair. The behaviour of mitochondrial DNA in the single cell gel electrophoresis assay has earlier been controversial, but it was shown herein that mitochondrial DNA diffuses away early in the assay. In contrast, Alu repeats remain associated with the nuclear matrix throughout the procedure. A new twelve gel approach was also developed with increased throughput of the single cell gel electrophoresis assay. DNA repair of three genes OGG1, XPD and HPRT and of Alu repeats after H2O2 induced damage was further monitored. All three genes and Alu repeats were repaired faster than total DNA. Finally, padlock probes and rolling circle amplification were applied for detection of the single stranded RNA virus Crimean Congo hemorrhagic fever virus. The virus was detected by first reverse transcribing RNA into cDNA.. The virus RNA together with its complementary RNA and the nucleocapsid protein were detected in cultured cells. The work presented here enables studies of gene specific damage and repair as well as viral infections in situ. Detection by ligation offers high specificity and makes it possible to discriminate even between closely related molecules. Therefore, these techniques will be useful for a wide range of applications within research and diagnostics.
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| 37. |
- Hjalmarsson, Anna, 1976-, et al.
(författare)
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Characteristic patterns of emergency ambulance assignments for older adults compared with adults requiring emergency care at home in Sweden : a total population study
- 2020
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Ingår i: BMC Emergency Medicine. - : BioMed Central. - 1471-227X. ; 20, s. 1-12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Since the vast majority of older adults in Sweden live in their private homes throughout life, the emergency medical services need to adapt accordingly. Hence, we aimed to describe characteristic patterns of dyadic staffed emergency ambulance assignments for older adults aged > 70 years compared with adults aged 18– 69 years requiring emergency care at home in Sweden.Methods: A descriptive retrospective study was performed using anonymized registry data from the emergency medical services in a region of Sweden during 2017–2018. One-sample χ2 test, one-way analysis of variance, and binary logistic regression models were used for investigating group differences. Variables for analysis were age, gender, clinical assessments, on-scene time, priority levels, result of response, and temporal patterns.Results: Of all included emergency ambulance assignments (n = 28,533), 59.9% involved older adults, of which 53.8% were women. The probability for older adults to receive the highest priority was decreased for both dispatch (p < 0.001, odds ratio [OR] 0.63, 95% confidence interval [CI] 0.59–0.66), and transport priorities (p < 0.001, OR 0.74, 95% CI 0.68–0.80). Older adults were more likely to receive dispatch priority levels 2 (p < 0.001, OR 1.48, 95% CI 1.40–1.56), and 3 (p < 0.001, OR 1.73, 95% CI 1.46–2.06). The older adults were similarly more likely to receive transport priority level 3 (p < 0.001, OR 1.40, 95% CI 1.28–1.52) compared with adults. Age had a small but additive effect in relation to on-scene time (p < 0.001, R2 = 0.01, F = 53.82). Distinguishing initial clinical assessments for older adults were circulatory, respiratory, trauma, infection, and nonspecific assessments. Emergency ambulance assignments for older adults were more frequently occurring on Mondays (p < 0.001, χ2 = 232.56), and in the 08:00– 11:59 interval (p < 0.001, χ2 = 1224.08).Conclusion: The issues of the lower priority level preponderance, and the decreased probability for receiving the highest priority warrant further attention in future research and clinical practice.
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| 38. |
- Keijser, Rebecka, 1984-
(författare)
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Depressive Symptoms Among Adolescents and Young Adults : Psychometrics and the Influence of Family Environment, and Candidate Gene–environment Interactions
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aims of this thesis were to evaluate the psychometric properties of a questionnaire designed to evaluate parenting styles, and to study how depressive symptoms among adolescents and young adults may vary depending on the family environment and candidate gene–environment interaction (cG×E).The study sample consisted of participants (born during 1997 or 1999), and their caregivers from the Survey of Adolescent Life in Västmanland Cohort Study. This thesis included data from 2012 when the participants were 13 and 15 years old (Wave I: DNA collection), 2015 at ages 16 and 18 years (Wave II: Parenting styles, parental depression, depressive symptoms, early life stress i.e., ELS) and 2018 at ages 19 and 21 years (Wave III: Depressive symptoms).Paper I: A good model fit was obtained for the Parent as Social Context Questionnaire (PASCQ) parent and adolescent versions through psychometric evaluations. Paper II: Positive and negative parenting styles were associated with fewer or more depressive symptoms among adolescents and young adults, respectively. Parental depression×sex was associated with more depressive symptoms, preponderant among female adolescents. The findings were not significant among young adults. Paper III: A significant cG×E effect between oxytocin receptor single-nucleotide polymorphism (SNP) rs6770632 and negative parenting style on depressive symptoms among young adults was found. Paper IV: Significant cG×E effects were found for the FKBP5 SNPs rs1360780, rs4713916, rs7748266 and rs9394309 moderated by ELS and positive parenting style on depressive symptoms among young adults.These findings suggest that parenting styles may be measured with the PASCQ and that depressive symptoms among adolescents and young adults seem to vary dependent on the family environment and cG×E effects. However, the cG×E effects may be more central for some individuals depending on differences in diathesis- or sensitivity towards the family environment. The variance in depressive symptoms may therefore contain diathesis stress and differential susceptibility effects regarding the cG×E interaction. The insight gained from this thesis provides a foundation for future research and contributes to research areas such as parenting research and the understanding of biological factors behind depressive symptomology among adolescents and young adults.
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| 39. |
- Krzywkowski, Tomasz, 1986-
(författare)
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iLocks: a novel tool for RNA assays with improved specificity
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Central Dogma of molecular biology describes a framework for how genetic information is transferred in cells, placing RNA as a messenger between DNA and translated proteins. During the last years, interest in RNA research has grown tremendously due to the increasing understanding and recognition of the importance of RNA in regulation of gene expression, biochemical catalysis, and genome integrity surveillance. Most importantly, RNA content, unlike DNA, changes constantly, fine-tuning the cellular response to match the environmental conditions. There is a clear potential for RNA biomarkers, reflecting both the natural and pathological conditions in vivo.Various methods have been developed to study RNA, of which the most common tools and techniques are described in this thesis. Since many of these gold standard methods are based on detecting RNA derivative (cDNA), there is a wide scope for efficient alternative tools directly targeting RNA. In Paper I, the spatiotemporal expression of human adenovirus-5 mRNA in epithelial and blood cells infected with the virus has been studied. For this, padlock probes and rolling circle amplification (RCA) were used to visualize, quantify and analyse both viral and host cell cDNAs in different infection scenarios, at single cell level. In Paper II, direct RNA detection fidelity has been evaluated using padlock probes. A novel type of probe (iLock) that is activated on RNA via invasive cleavage mechanism, prior to RCA was developed in this approach. Using iLocks, a substantial improvement of direct RNA sensing fidelity has been observed. In Paper III, RNA modifications were introduced in otherwise DNA iLock probes to enhance the probes’ efficiency on miRNAs. Using chimeric iLock probes, multiplexed differentiation of conserved miRNA family members were performed with next- generation sequencing-by-ligation readout. Efficient replication of chimeric probes used in Paper III implies that the Phi29 DNA polymerase readily accepts RNA-containing circles as amplification substrates. In Paper IV, real-time RCA monitoring for measurement of amplification rates and analysis of amplification patterns of various RNA-containing circles was achieved. Moreover, the RCA products were sequenced as a proof for the reverse-transcriptase activity of the Phi29 DNA polymerase.This thesis effectively contributes to a better understanding of mechanisms influencing RNA detection with, but not limited to, padlock probes. It expands the available RNA analyses toolkit with novel strategies and solutions, which can be potentially adapted for RNA-focused research, in general and molecular diagnostics, in particular.
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| 40. |
- Lindfeldt, Erik G., 1978-
(författare)
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A trinity of sense : Using biomass in the transport sector for climate change mitigation
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis analyses two strategies for decreasing anthropogenic carbon dioxide (CO2) emissions: to capture and store CO2, and to increase the use of biomass. First, two concepts for CO2 capture with low capture penalties are evaluated. The concepts are an integrated gasification combined cycle where the oxygen is supplied by a membrane reactor, and a hybrid cycle where the CO2 is captured at elevated pressure. Although the cycles have comparatively high efficiencies and low penalties, they illustrate the inevitable fact that capturing CO2 will always induce significant efficiency penalties. Other strategies are also needed if CO2 emissions are to be forcefully decreased. An alternative is increased use of biomass, which partially could be used for production of motor fuels (biofuels). This work examines arguments for directing biomass to the transport sector, analyses how biofuels (and also some other means) may be used to reduce CO2 emissions and increase security of motor fuel supply. The thesis also explores the possibility of reducing CO2 emissions by comparatively easy and cost-efficient CO2 capture from concentrated CO2 streams available in some types of biofuel plants. Many conclusions of the thesis could be associated with either of three meanings of the word sense: First, there is reason in biofuel production – since it e.g. reduces oil dependence. From a climate change mitigation perspective, however, motor fuel production is often a CO2-inefficient use of biomass, but the thesis explores how biofuels’ climate change mitigation effects may be increased by introducing low-cost CO2 capture. Second, the Swedish promotion of biofuels appears to have been governed more by a feeling for attaining other goals than striving for curbing climate change. Third, it seems to have been the prevalent opinion among politicians that the advantages of biofuels – among them their climate change mitigation benefits – are far greater than the disadvantages and that they should be promoted. Another conclusion of the thesis is that biofuels alone are not enough to drastically decrease transport CO2 emissions; a variety of measures are needed such as fuels from renewable electricity and improvements of vehicle fuel economy.
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| 41. |
- Lundin, Elin, 1983-
(författare)
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RNA-based spatial characterization of cell and tissue heterogeneity
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Technical advances in cell biology have revolutionized the field of cell biology. With new technology it is now possible to address scientific questions in cell biology at the molecular level. Single-cell RNA-sequencing can reveal transcriptomic information for single cells and spatially resolved transcriptomic technology can visualize thousands or millions of cells and transcripts for spatial molecular profiling. The work in this thesis describes the technological development from traditional in situ hybridization to the current state-of-the-art technology for spatial multiplexed gene expression analysis. This development has enabled RNA-based molecular characterization of cells and tissues with the spatial dimension maintained. The work included in the thesis highlights the potential and the advantages of padlock-probe-based technology for spatial RNA-based profiling of cells and tissues. Furthermore, it demonstrates the possibilities arising from the inherent ability of padlock probes to distinguish between transcripts based on differences in single nucleotides.The study in paper I investigates the prevalence of Enterovirus species B in patients with Crohn’s disease by a chromogenic in situ hybridization assay combined with immunohistochemistry to detect viral RNA and proteins directly in tissue samples.In paper II, padlock probes were used to study the spatial gene expression of gene homologs from the X and Y chromosome in human embryonic nervous tissue. Furthermore, a strategy was devised to visualize and evaluate spatial expression patterns.The padlock probe-based approach for multiplexed spatial transcriptional profiling, in situ sequencing, was applied in paper III to study the regional and cell-type-specific dynamics of A-to-I RNA editing in the developing mouse brain.In paper IV, a technical characterization of padlock probes was performed with the aim of determining how to design a padlock probe to obtain optimal detection efficiency.The work in this thesis demonstrates the dramatic shift in how biological questions in cell and tissue biology can be addressed, enabled by the technological evolution of traditional in situ hybridization assays into high-throughput, multiplexed spatial transcription profiling.
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| 42. |
- Lundström, Mats Johan, 1973-
(författare)
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Planering och hållbar bebyggelseutveckling i ett energi- och klimatperspektiv
- 2010
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ”Det kommunala planmonopolet” gör att kommunerna är viktiga aktörer i utmaningen att minska energianvändning och klimatpåverkan inom bebyggelse- och transportsektorerna, vilka står för en övervägande del av landets totala energianvändning. Den största potentialen i kommunernas planering och reglering av ny bebyggelse ligger i möjligheten att påverka bebyggelsens lokalisering och täthet, vilket har betydelse för resandets omfattning och val av transportsätt. Plan- och bygglagen (PBL) ger kommunerna vissa möjligheter att påverka energianvändningen och energitillförseln för ny bebyggelse, men de är tämligen begränsade. Variabler som mikroklimat och stadstyper med låg omslutningskvot påverkar bebyggelsens energianvändning i ett byggnadsfysiskt perspektiv, men ur ett administrativt perspektiv spelar detta ingen roll sedan energikraven i Boverkets byggregler sedan några år tillbaka ställer krav på hela byggnadens energiprestanda och inte på enskilda byggnadsdelar. Om byggreglernas krav istället skulle gälla byggnadens energianvändning i ett livscykelperspektiv skulle detta ge en mer rättvis bild samtidigt som planeringsfrågor som placering av bebyggelse och samt stadstyper skulle påverka energianvändningen. Vidare efterfrågas riktlinjer för hur användningen av elektricitet i bebyggelsesektorn ska miljöbedömas samt en statlig samsyn om elens roll ibland annat uppvärmnings- och transportsektorerna.Den stora effektiviseringspotentialen i bebyggelsesektorn finns dock i den befintliga bebyggelsen, vilket inte kan styras med vare sig markanvändningsreglering enligt PBL-planeringen eller Boverkets byggregler – det är fastighetsägarnas ansvar. Men planering kan omfatta så mycket mer än bara reglering. PBL:s organisation och krav på samrådsprocesser gör den kommunala planeringen till en viktig utvecklingsarena där såväl fastighetsägare som andra aktörer kan bjudas in att delta. Istället för ett traditionellt tvingande uppifrånperspektiv skulle den kommunala planeringen i högre grad kunna inta ett underifrånperspektiv och arbeta mer positivt och visa på möjligheterna att minska energianvändningen och få en mer hållbar energitillförsel, frågor som är bra både ur ett miljö- som ekonomiskt perspektiv. Planeringen skulle vidare behöva bli mer strategisk och genomförandeinriktad.I forsknings- och utvecklingsprogrammet Uthållig kommun fysisk planering har nya planeringsmetoder och -verktyg introducerats i fem kommuner, med syfte att integrera energi- och hållbarhetsaspekterna i den kommunala fysiska planeringen. En studie av den introducerade arbetsmetodiken visar att det går bra att kombinera rationella och kommunikativa planeringsmetoder och -verktyg. Det breda och inkluderande tillvägagångssättet har lett till att de deltagande har ökat sin kunskap om och sett större samband mellan planering, energi, bebyggelse och transporter, men även ökad förståelse för andra aktörers synsätt och kompetenser. Studien visar att såväl rationellt tänkande och expertkunskap som lokala, vardagliga erfarenheter och kunskaper är viktiga i planeringsprocessen. Det behövs kunskap om såväl processledning som sakkunskaper om exempelvis energi och miljöpåverkan.
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| 43. |
- Mezger, Anja, 1986-
(författare)
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Padlock Probe-Based Assays for Molecular Diagnostics
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Treatment success often depends on the availability of accurate and reliable diagnostic assays to guide clinical practitioners in their treatment choices. An optimal test must excel in specificity and sensitivity, and depending on the application area time, low-cost and simplicity are equally important. For instance, time is essential in infectious diagnostics but this is less important in non-invasive prenatal testing (NIPT). In NIPT, specificity and sensitivity are the most important parameters.In this thesis I describe the development of four different methods, all based on padlock probes and rolling circle amplification, intended for molecular diagnostics. Application areas range from infectious disease diagnostics to NIPT and oncology. The methods described have in common that they overcome certain limitations of currently available assays. This thesis includes two new assays targeting infectious agents: one assay specifically detecting a highly variable double stranded RNA virus and the second assay demonstrating a new format of antibiotic susceptibility testing, which is rapid and generally applicable to different pathogens. Furthermore, I describe the development of a method that uses methylation markers to enrich fetal DNA, accurately quantify chromosome ratios and thus, detecting trisomy 21 and 18. The fourth method described in this thesis uses gap-fill ligation of padlock probes to detect diagnostic relevant point mutations with high specificity in situ.The assays presented have the potential, after automation and successful validation and verification studies, to be implemented into clinical practice. Furthermore, these assays demonstrate the wide applicability of padlock probes which, due to their properties in regard to specificity and multiplexity, are useful tools for nucleic acid detection in vitro as well as in situ.
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| 44. |
- Mignardi, Marco, 1981-
(författare)
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In situ Sequencing : Methods for spatially-resolved transcriptome analysis
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is well known that cells in tissues display a large heterogeneity in gene expression due to differences in cell lineage origin and variation in the local environment at different sites in the tissue, a heterogeneity that is difficult to study by analyzing bulk RNA extracts from tissue. Recently, genome-wide transcriptome analysis technologies have enabled the analysis of this variation with single-cell resolution. In order to link the heterogeneity observed at molecular level with the morphological context of tissues, new methods are needed which achieve an additional level of information, such as spatial resolution.In this thesis I describe the development and application of padlock probes and rolling circle amplification (RCA) as molecular tools for spatially-resolved transcriptome analysis. Padlock probes allow in situ detection of individual mRNA molecules with single nucleotide resolution, visualizing the molecular information directly in the cell and tissue context. Detection of clinically relevant point mutations in tumor samples is achieved by using padlock probes in situ, allowing visualization of intra-tumor heterogeneity. To resolve more complex gene expression patterns, we developed in situ sequencing of RCA products combining padlock probes and next-generation sequencing methods. We demonstrated the use of this new method by, for the first time, sequencing short stretches of transcript molecules directly in cells and tissue. By using in situ sequencing as read-out for multiplexed padlock probe assays, we measured the expression of tens of genes in hundreds of thousands of cells, including point mutations, fusions transcripts and gene expression level.These molecular tools can complement genome-wide transcriptome analyses adding spatial resolution to the molecular information. This level of resolution is important for the understanding of many biological processes and potentially relevant for the clinical management of cancer patients.
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| 45. |
- Neumann, Felix, 1989-
(författare)
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Advancing isothermal nucleic acid amplification tests : Towards democratization of diagnostics
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Modern healthcare is the result of scientific advancement across disciplines and has enabled us to understand the rationale behind many diseases and how to treat or cure them; but still a myriad of unanswered questions remains. Especially infectious diseases play an important role in healthcare as they pose a constant threat for global health and well-being. This was painfully highlighted in this year's ongoing COVID-19 pandemic with more than 40 million people infected and over 1 million deaths. Pandemics like this have not only devastating effects on global health but also economy.Therefore, scientific research in the field of infectious diseases is paramount to ensure outbreak control and surveillance of emerging threats. Current healthcare relies heavily on the diagnosis of infectious diseases in centralized healthcare centers thereby overlooking the access of molecular diagnostics for other areas such as airports, home-testing and especially the developing world with its limited resources. Towards this, various isothermal nucleic acid amplification technologies have been developed that hold the promise to bring state-of-the-art molecular diagnostics into these areas as they are versatile, sensitive and specific, and cost-effective. One such technique is rolling circle amplification which was used in this thesis.This research work provides an overview of the developments in biochemistry, related disciplines and their combination to design methods for diagnostic platforms tackling infectious diseases. The studies conducted in this work can be considered as individual modules for addressing challenges, like typing of pathogens and disease-related antibodies, and inexpensive bulk as well as digital quantification and simplified assay schemes. These approaches and their combinations aim to bring rolling circle amplification-based assay schemes into the molecular diagnostic field and towards decentralized healthcare.
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| 46. |
- Nilsson, Josefin A., 1985-
(författare)
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Juvenile birch in Sweden : Selected stem characteristics for interior and furniture applications
- 2019
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In response to the furniture industry’s growing demand for raw material, large volumes of juvenile silver birch and downy birch stems available from pre-commercial thinning operations in Sweden’s forests could offer solutions. However, such stems are not currently used on an industrial scale, and most research conducted on birch stems in general has neither focussed on young trees nor the potential use of the central stem part around the tree pith. The resulting lack of knowledge about the juvenile part of birch wood thus requires additional information about the material properties of birch, which could encourage its use for various purposes in the furniture and other industries.The initial literature review performed for this thesis has highlighted some properties of juvenile birch required for its use as a furniture material, as well as identified topics concerning the physical characteristics of juvenile birch about which knowledge is currently limited. Consequently, the objectives of this thesis were to explore some characteristics of juvenile birch—bark thickness, wood-to-bark bonding ratio after drying, variations in the density and width of growth rings, and anatomical growth response to fertilisation—in order to increase the knowledge.The material studied came from mixed birch and Norway spruce stands at two sites in southern Sweden, namely Asa and Toftaholm. The birch stems were naturally regenerated silver birch and downy birch, with breast height diameters between 30 and 83 mm. Fertilised and unfertilised silver birch trees were sampled at Toftaholm, whereas unfertilised stems of silver birch and downy birch were sampled at Asa. The characteristics of stems from the pith to bark (radial direction) and along the stem (longitudinal direction) were measured. The wood-to-bark bonding ratio on downy birch after drying was calculated as the percentage of the stem circumference with full contact between the wood and bark, while oven-dry density and basic wood density for silver birch were determined by using the water displacement method. The impact of ring width on wood density was statistically analysed, and an image analysis of the wood anatomy was conducted to elucidate their relationship.Amongst the results, bark thickness along the stem had the highest deviation in the section closest to the stump. Moreover, the wood-to-bark bonding ratio after drying measured for juvenile downy birch seemed to depend more on the stem’s diameter than the sampling height along the stem. Such results are relevant for processors seeking to estimate the volume of wood under the bark. The wood-to-bark bonding ratio was highest for diameters between 30 and 39 mm, and neither did that relationship correlate with the sampling height along the stem.Variation in wood density in the radial and longitudinal directions in juvenile silver birch suggested that such density negatively correlated with growth rate (ring width). That relationship held true for stems at each site and between the sites, irrespective of management or growing conditions. As expected, mean wood density was lower in fertilised trees than in unfertilised ones, and towards the bark, radial density increased more in trees that grew more slowly. At the same time, variation in longitudinal density in young silver birch trees was low. Quantitative wood anatomy studies confirmed that the fertilised juvenile birch had younger cambia, thinner cell walls, and fewer vessels per mm2 than unfertilised trees in the same diameter class.Overall, the knowledge generated in the study may facilitate the industrial use of juvenile birch stems and wood in interior and furniture applications. The role of wood anatomy in determining the mechanical performance of juvenile birch stems should be further examined, however, to possibly reveal new opportunities for the use of juvenile birch.
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| 47. |
- Nilsson, Kristina, 1986-
(författare)
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Oxidative dissolution of doped UO2 and H2O2 reactivity towards oxide surfaces : A kinetic and mechanistic study
- 2014
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Oxidative dissolution of std. UO2 and UO2 doped with Cr2O3 and Al2O3, i.e. ADOPT, induced by H2O2 and γ radiation has been the main focus in this licentiate thesis. The catalytic decomposition of H2O2 on oxides like Gd2O3, HfO2, CeO2, Fe2O3 and CuO were also investigated.A kinetic study was performed by determining first and second order rate constants together with Arrhenius parameters for the decomposition of H2O2. The reactivity of H2O2 towards the oxides mentioned was observed to differ significantly despite their similarities. In the mechanistic study, the yields and dynamics of the formation of the intermediate hydroxyl radical from the decomposition of H2O2 was determined for the oxides and found to differ considerably. A turnover point could be found for most of oxides studied, i.e. an increase in the rate of hydroxyl radical scavenging after a specific amount of consumed H2O2.The reactivity of the std. UO2 and ADOPT towards H2O2 was similar to what was observed for other UO2-based materials in previous studies. The oxidative dissolution in radiation experiments showed a slight but significant difference. This was attributed to a difference in exposed surface area instead of an effect of doping. The difference in oxidative dissolution yield was too small to be significant which supports the previous conclusion.Leaching experiments using spent nuclear fuel were also performed on the two types of fuel showing the same behavior as the unirradiated pellets, i.e., a slightly lower 238U release from ADOPT. The difference was attributed to difference in exposed surface area. The release of fission products with low UO2 solubility displayed a higher release from ADOPT which was attributed to a difference in matrix solubility. Cs was released to a larger extent from std. UO2. This is attributed to the larger grain size of ADOPT, extending the diffusion distance. The release of lanthanides and actinides was slightly higher for the conventional UO2, nevertheless the difference was relatively small.
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| 48. |
- Nilsson, Mats, 1971-
(författare)
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A Helping Hand : On Innovations for Rehabilitation and Assistive Technology
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on assistive and rehabilitation technology for restoring the function of the hand. It presents three different approaches to assistive technology: one in the form of an orthosis, one in the form of a brain-computer interface combined with functional electrical stimulation and finally one totally aiming at rehabilitating the nervous system by restoring brain function using the concept of neuroplasticity. The thesis also includes an epidemiological study based on statistics from the Swedish Hospital Discharge Register and a review on different methods for assessment of hand function.A novel invention of an orthosis in form of a light weight glove, the SEM (Soft Extra Muscle) glove, is introduced and described in detail. The SEM glove is constructed for improving the grasping capability of a human independently of the particular task being performed. A key feature is that a controlling and strengthening effect is achieved without the need for an external mechanical structure in the form of an exoskeleton. The glove is activated by input from tactile sensors in its fingertips and palm. The sensors react when the applied force is larger than 0.2 N and feed a microcontroller of DC motors. These pull lines, which are attached to the fingers of the glove and thus work as artificial tendons.A clinical study on the feasibility of the SEM glove to improve hand function on a group of patients with varying degree of disability has been made. Assessments included passive and active range of finger motion, flexor muscle strength according to the Medical Research Council (MRC) 0-5 scale, grip strength using the Grippit hand dynamometer, fine motor skills according to the Nine Hole Peg test and hand function in common activities by use of the Sollerman test. Participants rated the potential benefit on a Visual Analogue Scale.A prototype for a system for combining BCI (Brain-Computer Interface) and FES (Functional Electrical Stimulation) is described. The system is intended to be used during the first period of recovery from a TBI (Traumatic Brain Injury) or stroke that have led to paresis in the hand, before deciding on a permanent system, thus allowing the patients to get a quick start on the motor relearning. The system contains EEG recording electrodes, a control unit and a power unit. Initially the patients will practice controlling the movement of a robotic hand and then move on to controlling pulses being sent to stimulus electrodes placed on the paretic muscle.An innovative electrophysiological device for rehabilitation of brain lesions is presented, consisting of a portable headset with electrodes on both sides adapted on the localization of treatment area. The purpose is to receive the outgoing signal from the healthy side of the brain and transfer that signal to the injured and surrounding area of the remote side, thereby having the potential to facilitate the reactivation of the injured brain tissue. The device consists of a control unit as well as a power unit to activate the circuit electronics for amplifying, filtering, AD-converting, multiplexing and switching the outgoing electric signals to the most optimal ingoing signal for treatment of the injured and surrounding area.
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| 49. |
- Nilsson, Mats
(författare)
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Assessment of Drug-Induced Cardiotoxicity during Rat Embryo Development
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The potassium ion channel (hERG/IKr) is important for normal heart function and drug-induced blockade of the channel in adult humans can lead to irregular heart rhythms (arrhythmia). The ion channel is also essential for early cardiac function in the embryo and therapeutic drugs which block this channel have been shown to cause birth defects in animal studies. A wide range of birth defects have been seen including cleft lip/palate, distal limb defects and heart malformations.These malformations are associated with periods of hypoxia and altered blood flow in the embryo associated with the drug-induced heart rhythm disorders and bradycardia. It is also well known that other experimental procedures causing periods of hypoxia in the embryo can give rise to similar defects as those seen with drugs that block the hERG/IKr channel. Paper I on the thesis deals with risk assessment for use in pregnancy of drugs which block hERG/IKr. Evaluation of the risk of birth defects is largely based on the results of experimental studies on animals. Guidelines for how such standard tests are to be performed were determined by regulatory authorities several decades ago. However, there are examples where safety studies for drugs blocking hERG/IKr, although fulfilling regulatory guidelines, have been carried out at a suboptimal dose range and failed to detect teratogenicity. A consequence of this is that the teratogenic potential of hERG/IKr blocking drugs have been missed in standard safety testing. The results of the paper I show that the teratogenic properties of the drug astemizole (withdrawn from the market several years ago because of fatal cardiac arrhythmias in adults related to the blockade of hERG/IKr) were missed in the initial safety studies.Paper II shows that several drugs that block cardiac ion channels other than hERG/IKr can also disrupt fetal cardiac function during embryonic development. However, the concentrations required to cause these changes are much higher than is likely to occur during normal use of the medicines and based on these results that are not considered a risk when taken during pregnancy.Paper III deals with the possible teratogenicity of erythromycin. From the Swedish Birth Defects Register there have been signals that use of erythromycin (which has hERG/IKr-blocking properties) during pregnancy is associated with an increased risk of cardiovascular malformations. Paper III shows that the levels of erythromycin needed to disrupt fetal cardiac function during embryonic development are unlikely to occur after normal oral treatment with erythromycin.Paper IV shows that the embryonic rat heart undergoes major changes in sensitivity to blockade of specific cardiac ion channels during the organogenic period. This is an important observation from the perspective that there may be periods during embryonic development when the embryo is more or less sensitive to the effect of drugs that affect specific ion channels.To conclude, papers I-IV show that the study of drug effects on the gestation day 13 rat embryonic heart, together with the use of computational assisted image analysis of the cardiac response, provides an in vitro model for hazard identification of compounds with the potential to adversely affect heart function in the developing embryo.
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| 50. |
- Nilsson, Mats
(författare)
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Post-Secular Tourism : A Study of Pilgrimages to Santiago de Compostela
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis takes its starting-point in the post-secular changes in society and how these interplay with tourism. In spite of the intensive academic debate on and theorisation of the post-secular and post-secularism, the role of tourism in this change, called the return of religion, has not been studied. Conversely, neither has the role of post-secularism in tourism been addressed. The overall aim of this thesis is to describe and understand the relation between post-secularism and tourism. Specifically, the aim is to clarify and understand the relation between religious faith, place and tourism in our time on the basis of a case study of pilgrimage in the area of Santiago de Compostela. In other words, the thesis highlights the role of tourism in the emergence of what is now called the post-secular condition.Santiago de Compostela is a Catholic Church instituted holy city, which has increase in number of visitors. The growing number of pilgrimages and their significance lend vitality to the return of religion phenomenon. The empirical material derives primarily from individual interviews as narratives are considered to be a vital dimension to constitute and construct human realities and modes of being.This thesis shows that contemporary pilgrimage to Santiago de Compostela is a post-secular performative and place-creating phenomenon. Post-secular tourist places are subjective and spiritually meaningful destinations. Unlike traditional pilgrimage destinations a key attribute is that neither traditional religious faith nor loyalty to institutionalised faith are (pre)ordained. Rather, place is constructed by the narratives and experiences of post-secular tourists.
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