| 1. |
- Norberg, Maria, 1976-
(författare)
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In Vitro Drug Sensitivity and Apoptosis in Chronic Lymphocytic Leukemia
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic lymphocytic leukemia (CLL) is a heterogeneous malignancy displaying varying clinical outcome, where molecular markers today can divide patients into prognostic subgroups. Despite the introduction of new agents for treatment, remissions are usually not sustained in CLL and resistance towards treatment can partly be explained by aberrant apoptosis. The aim of this thesis was to find new drugs for CLL patients resistant to conventional therapy and to analyze genes involved in apoptosis within different prognostic subgroups. In paper I-II, the in vitro activity of substances was investigated using the fluorometric microculture cytotoxicity assay (FMCA). When evaluating rapamycin (paper I), an inhibitor of mTOR, in 97 tumor samples from different entities, CLL was found to be one of the most sensitive tumor types. Combination experiments on patient CLL cells indicated that rapamycin acted synergistically with the CLL drugs vincristine and chlorambucil. An investigation of 20 anti-cancer agents in cells from 40 CLL patients (paper II) revealed that prednisolone and rolipram displayed high activity in poor-prognostic patients, in particular IGHV unmutated CLL. Furthermore, when used in combination these agents were found to produce a synergistic effect. In paper III, the anti-apoptotic BCL2 family member BFL1 was evaluated in 37 CLL cases. Levels of BFL1 were higher in fludarabine-resistant patients compared to fludarabine-sensitive patients. In addition, the high expression of BFL1 inversely correlated to fludarabine-induced apoptosis in CLL cells. A single nucleotide polymorphism in the anti-apoptotic BCL2 gene (-938C>A) has been suggested as a novel poor-prognostic marker in CLL. In paper IV, we investigated this BCL2 polymorphism in 268 CLL patients and correlated genotypes to clinical data. However, no association could be confirmed between this polymorphism and clinical outcome or established prognostic markers. In conclusion, this thesis has shown that rapamycin is a potential drug for treatment in CLL. Furthermore, prednisolone and rolipram were identified as interesting candidates for treatment of poor-prognostic patients. Finally, the anti-apoptotic protein BFL1 may contribute to chemoresistance and hence represents a potential therapeutic target in CLL, whereas from our data, the BCL2 -938C>A polymorphism does not appear to have any prognostic significance.
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| 2. |
- Carlfjord, Siw, 1959-
(författare)
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The Challenge of Changing Practice : Applying Theory in the Implementation of an Innovation in Swedish Primary Health Care
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The translation of new knowledge, such as research findings, new tools or methods into health care practice has gained increased interest in recent years. Important factors that determine implementation outcome have been identified, and models and checklists to be followed in planning as well as in carrying out an implementation process have been produced. However, there are still knowledge gaps regarding what approach should be used in which setting and for which problems. Primary health care (PHC) in Sweden is an area where there is a paucity of research regarding implementation of new methods into practice. The aim of the thesis was to apply theory in the study of the implementation of an innovation in Swedish PHC, and identify factors that influenced outcome.Methods: The study was performed using a quasi-experimental design, and included six PHC units, two from each one of three county councils in the southeast part of Sweden. A computer-based lifestyle intervention tool (CLT) developed to facilitate addressing lifestyle issues, was introduced at the units. Two different strategies were used for the introduction, both aiming to facilitate the process: a theory-based explicit strategy and an implicit strategy requiring a minimum of effort. Data collection was performed at baseline, and after six, nine and 24 months. Questionnaires were distributed to staff and managers, and data was also collected from the CLT database and county council registers. Implementation outcome was defined as the proportion of eligible patients being referred to the CLT, and was also measured in terms of Reach, Effectiveness, Adoption, Implementation and Maintenance according to the RE-AIM framework. Interviews were performed in order to explore experiences of the implementation process as perceived by staff and managers.Results: A positive organizational climate seemed to promote implementation. Organizational changes or staff shortages coinciding with the implementation process had a negative influence on outcome. The explicit implementation strategy seemed to be more effective than the implicit strategy in the short term, but the differences levelled out over time. The adopters’ perceptions of the implementation seemed to be influenced by the existing professional sub-cultures. Successful implementation was associated with positive expectations, perceptions of the innovation being compatible with existing routines and perceptions of relative advantage.Conclusions: The general conclusion is that when theory was applied in the implementation of a lifestyle intervention tool in Swedish PHC, factors related to the adopters and to the innovation seemed to be more important over time than the strategy used. Staff expectations, perceptions of the innovation’s relative advantage and potential compatibility with existing routines were found to be positively associated with implementation outcome, and other major organizational changes concurrent with implementation seemed to affect the outcome in a negative way. Values, beliefs and behaviour associated with the existing sub-cultures in PHC appeared to influence how the implementation of an innovation was perceived by managers and the different professionals.
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| 3. |
- Afrasiabi, Roodabeh, et al.
(författare)
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Integration of a droplet-based microfluidic system and silicon nanoribbon FET sensor
- 2016
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Ingår i: Micromachines. - : MDPI AG. - 2072-666X. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- We present a novel microfluidic system that integrates droplet microfluidics with a silicon nanoribbon field-effect transistor (SiNR FET), and utilize this integrated system to sense differences in pH. The device allows for selective droplet transfer to a continuous water phase, actuated by dielectrophoresis, and subsequent detection of the pH level in the retrieved droplets by SiNR FETs on an electrical sensor chip. The integrated microfluidic system demonstrates a label-free detection method for droplet microfluidics, presenting an alternative to optical fluorescence detection. In this work, we were able to differentiate between droplet trains of one pH-unit difference. The pH-based detection method in our integrated system has the potential to be utilized in the detection of biochemical reactions that induce a pH-shift in the droplets.
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| 4. |
- Andren, Per, et al.
(författare)
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Efficacy and cost-effectiveness of therapist-guided internet-delivered behaviour therapy for children and adolescents with Tourette syndrome : study protocol for a single-blind randomised controlled trial
- 2021
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Ingår i: Trials. - : BioMed Central (BMC). - 1745-6215. ; 22
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Tidskriftsartikel (refereegranskat)abstract
- Background: Treatment guidelines recommend behaviour therapy (BT) for patients with Tourette syndrome (TS) and chronic tic disorder (CTD). However, BT is rarely accessible due to limited availability of trained therapists and long travel distances to specialist clinics. Internet-delivered BT has the potential of overcoming these barriers through remote delivery of treatment with minimal therapist support. In the current protocol, we outline the design and methods of a randomised controlled trial (RCT) evaluating an internet-delivered BT programme referred to as BIP TIC. The trial's primary objective is to determine the clinical efficacy of BIP TIC for reducing tic severity in young people with TS/CTD, compared with an active control intervention. Secondary objectives are to investigate the 12-month durability of the treatment effects and to perform a health economic evaluation of the intervention.Methods: In this single-blind superiority RCT, 220 participants (9-17 years) with TS/CTD throughout Sweden will be randomised to 10-12 weeks of either therapist-supported internet-delivered BT based on exposure with response prevention (BIP TIC) or therapist-supported internet-delivered education. Data will be collected at baseline, 3 and 5 weeks into the treatment, at post-treatment, and 3, 6, and 12 months post-treatment. The primary endpoint is the 3-month follow-up. The primary outcome is tic severity as measured by the Yale Global Tic Severity Scale - Total Tic Severity Score. Treatment response is operationalised as scores of "Very much improved" or "Much improved" on the Clinical Global Impression - Improvement scale, administered at the primary endpoint. Outcome assessors will be blind to treatment condition at all assessment points. A health economic evaluation of BIP TIC will be performed, both in the short term (primary endpoint) and the long term (12-month follow-up). There are no planned interim analyses.Discussion: Participant recruitment started on 26 April 2019 and finished on 9 April 2021. The total number of included participants was 221. The final participant is expected to reach the primary endpoint in September 2021 and the 12-month follow-up in June 2022. Data analysis for the primary objective will commence after the last participant reaches the primary endpoint.
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| 5. |
- Andrén, Per, et al.
(författare)
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Internet-Delivered Exposure and Response Prevention for Pediatric Tourette Syndrome : 12-Month Follow-Up of a Randomized Clinical Trial
- 2024
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Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Behavior therapy is a recommended intervention for Tourette syndrome (TS) and chronic tic disorder (CTD), but availability is limited and long-term effects are uncertain.OBJECTIVE: To investigate the long-term efficacy and cost-effectiveness of therapist-supported, internet-delivered exposure and response prevention (ERP) vs psychoeducation for youths with TS or CTD.DESIGN, SETTING, AND PARTICIPANTS: This 12-month controlled follow-up of a parallel group, superiority randomized clinical trial was conducted at a research clinic in Stockholm, Sweden, with nationwide recruitment. In total, 221 participants aged 9 to 17 years with TS or CTD were enrolled between April 26, 2019, and April 9, 2021, of whom 208 (94%) provided 12-month follow-up data. Final follow-up data were collected on June 29, 2022. Outcome assessors were masked to treatment allocation throughout the study.INTERVENTIONS: A total of 111 participants were originally randomly allocated to 10 weeks of therapist-supported, internet-delivered ERP and 110 participants to therapist-supported, internet-delivered psychoeducation.MAIN OUTCOMES AND MEASURES: The primary outcome was within-group change in tic severity, measured by the Total Tic Severity Score of the Yale Global Tic Severity Scale (YGTSS-TTSS), from the 3-month follow-up to the 12-month follow-up. Treatment response was defined as 1 (very much improved) or 2 (much improved) on the Clinical Global Impression-Improvement scale. Analyses were intention-to-treat and followed the plan prespecified in the published study protocol. A health economic evaluation was performed from 3 perspectives: health care organization (including direct costs for treatment provided in the study), health care sector (additionally including health care resource use outside of the study), and societal (additionally including costs beyond health care [eg, parent's absenteeism from work]).RESULTS: In total, 221 participants were recruited (mean [SD] age, 12.1 [2.3] years; 152 [69%] male). According to the YGTSS-TTSS, there were no statistically significant changes in tic severity from the 3-month to the 12-month follow-up in either group (ERP coefficient, -0.52 [95% CI, -1.26 to 0.21]; P = .16; psychoeducation coefficient, 0.00 [95% CI, -0.78 to 0.78]; P > .99). A secondary analysis including all assessment points (baseline to 12-month follow-up) showed no statistically significant between-group difference in tic severity from baseline to the 12-month follow-up (coefficient, -0.38 [95% CI, -1.11 to 0.35]; P = .30). Treatment response rates were similar in both groups (55% in ERP and 50% in psychoeducation; odds ratio, 1.25 [95% CI, 0.73-2.16]; P = .42) at the 12-month follow-up. The health economic evaluation showed that, from a health care sector perspective, ERP produced more quality-adjusted life years (0.01 [95% CI, -0.01 to 0.03]) and lower costs (adjusted mean difference -$84.48 [95% CI, -$440.20 to $977.60]) than psychoeducation at the 12-month follow-up. From the health care organization and societal perspectives, ERP produced more quality-adjusted life years at higher costs, with 65% to 78% probability of ERP being cost-effective compared with psychoeducation when using a willingness-to-pay threshold of US $79 000.CONCLUSIONS AND RELEVANCE: There were no statistically significant changes in tic severity from the 3-month through to the 12-month follow-up in either group. The ERP intervention was not superior to psychoeducation at any time point. While ERP was not superior to psychoeducation alone in reducing tic severity at the end of the follow-up period, ERP is recommended for clinical implementation due to its likely cost-effectiveness and support from previous literature.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03916055.
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| 6. |
- Andrén, Per, et al.
(författare)
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Therapist-Supported Internet-Delivered Exposure and Response Prevention for Children and Adolescents with Tourette Syndrome : A Randomized Clinical Trial
- 2022
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Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 5:8
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: The availability of behavior therapy for individuals with Tourette syndrome (TS) and chronic tic disorder (CTD) is limited.OBJECTIVE: To determine the efficacy and cost-effectiveness of internet-delivered exposure and response prevention (ERP) for children and adolescents with TS or CTD.DESIGN, SETTING, AND PARTICIPANTS: This single-masked, parallel group, superiority randomized clinical trial with nationwide recruitment was conducted at a research clinic in Stockholm, Sweden. Out of 615 individuals assessed for eligibility, 221 participants meeting diagnostic criteria for TS or CTD and aged 9 to 17 years were included in the study. Enrollment began in April 2019 and ended in April 2021. Data were analyzed between October 2021 and March 2022.INTERVENTIONS: Participants were randomized to 10 weeks of therapist-supported internet-delivered ERP for tics (111 participants) or to therapist-supported internet-delivered education for tics (comparator group, 110 participants).MAIN OUTCOMES AND MEASURES: The primary outcome was change in tic severity from baseline to the 3-month follow-up as measured by the Total Tic Severity Score of the Yale Global Tic Severity Scale (YGTSS-TTSS). YGTSS-TTSS assessors were masked to treatment allocation. Treatment response was operationalized as a score of 1 ("Very much improved") or 2 ("Much improved") on the Clinical Global Impression-Improvement scale.RESULTS: Data loss was minimal, with 216 of 221 participants (97.7%) providing primary outcome data. Among randomized participants (152 [68.8%] boys; mean [SD] age, 12.1 [2.3] years), tic severity improved significantly, with a mean reduction of 6.08 points on the YGTSS-TTSS in the ERP group (mean [SD] at baseline, 22.25 [5.60]; at 3-month follow-up, 16.17 [6.82]) and 5.29 in the comparator (mean [SD] at baseline, 23.01 [5.92]; at 3-month follow-up, 17.72 [7.11]). Intention-to-treat analyses showed that the 2 groups improved similarly over time (interaction effect, -0.53; 95% CI, -1.28 to 0.22; P = .17). Significantly more participants were classified as treatment responders in the ERP group (51 of 108 [47.2%]) than in the comparator group (31 of 108 [28.7%]) at the 3-month follow-up (odds ratio, 2.22; 95% CI, 1.27 to 3.90). ERP resulted in more treatment responders at little additional cost compared with structured education. The incremental cost per quality-adjusted life-year gained was below the Swedish willingness-to-pay threshold, at which ERP had a 66% to 76% probability of being cost-effective.CONCLUSIONS AND RELEVANCE: Both interventions were associated with clinically meaningful improvements in tic severity, but ERP led to higher response rates at little additional cost.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03916055.
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| 7. |
- Katsogiannos, Petros, 1979-
(författare)
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Bariatric surgery as treatment of type 2 diabetes – clinical and mechanistic aspects
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bariatric surgery can rapidly improve glycemic control and cardiovascular risk factors in patients with T2D and obesity. These improvements appear to be partly independent of weight loss, however, the underlying mechanisms remain incompletely understood. A randomized controlled trial was designed where 19 patients with obesity and T2D were either operated with a Roux-en-Y gastric bypass (RYGB) operation or continued with standard-of-care treatment and followed up for 2 years, providing the data for Paper I-III.In paper I, we focused on changes in whole-body glucose metabolism in relation to changes in adipose tissue metabolism and morphology. We observed an early adipose tissue remodeling and a reduction in adipocyte size that however, did not correlate to the early improvements in metabolic control.In paper II, we analyzed the neuroendocrine changes after RYGB. We observed changes within 4 weeks with signs of enhanced parasympathetic outlow, reduced morning cortisol, and enhanced incretin and glucagon responses to glucose, suggesting that neurohormonal mechanisms can contribute to the rapid improvement of insulin resistance and glycemia following RYGB in T2D.In paper III the patients from the RYGB group were interviewed 2 years after surgery to examine the effects of surgery on health-related quality of life (HRQoL). We found that the improved HRQoL after RYGB was not explained specifically by the magnitude of weight loss, but rather by the participants achieving a state of union between body and consciousness.In paper IV, we compared changes in circulating cytokine and adipokine levels in obese patients with- and without T2D. We observed that the cytokine profile of these patients is altered when compared to lean healthy control subjects and persist to a large extent after RYGB despite the weight loss and improved metabolic status.In conclusion, we observed that in the early post-operative period, neurohormonal changes appear to be more important than adipose tissue changes in improving insulin sensitivity and leading to diabetes remission.In the qualitative part of our study, we observed that the improved HRQoL was not solely explained by weight loss
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| 8. |
- Kutscher, Liselott, 1976-
(författare)
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Export and sources of organic carbon in the Lena River basin, Northeastern Siberia
- 2016
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Permafrost areas are considered to be one of the largest terrestrial storages of carbon. In a warming climate these areas are expected to experience changes in carbon transport to rivers and the oceans due to permafrost thawing, which could enhance erosion, change water flow pathways and increase greenhouse gas emissions. Large amounts of the carbon transported from the terrestrial environment to rivers are in the form of natural organic matter (NOM). The Lena River basin in northeastern Siberia, which is mainly underlain by continuous permafrost, is the largest contributor of NOM to the Arctic Ocean. In this study we present a spatial data set of NOM, including concentrations and stable carbon isotope values (δ13C) of dissolved (DOC) and particulate organic carbon (POC) as well as carbon and nitrogen ratios (C/N) from 77 sample stations in the Lena River and its tributaries. The samples were collected during two field seasons in July 2012 and June 2013.The results from this study showed large spatial variations in concentrations, annual export and fluxes of organic carbon. These variations were primarily due to variations in discharge and topography. The δ13C and C/N indicated that terrestrial sources such as plants and soil organic matter (SOM), were the main sources of the dissolved organic matter (DOM), while particulate organic matter (POM) was mainly derived from aquatic produced material or SOM. There were clear differences in δ13C and C/N of DOM between sampling years, indicating more surficial flow pathways in samples collected earlier in the summer compared to samples collected later in the summer. The δ13C of POM was correlated with water temperatures and topography, showing that tributaries with origin in mountainous areas in general had soil derived POM and lower water temperatures, while tributaries from lowland areas had higher water temperatures and more influence of aquatic sources. We suggest that this pattern is probably due to differences in water flow pathways. Shifts in export of NOM from drainage areas underlain by permafrost will likely be dependent of spatial changes in hydroclimate and the depth of the active layer in a warming climate.
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| 9. |
- Reghellin, Daniele, 1984-
(författare)
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Paleoceanography of the Eastern Equatorial Pacific over the last eight million years
- 2013
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many studies have investigated the evolution of the Eastern Equatorial Pacific (EEP) Ocean paleoceanography since the late Neogene because of its role in regulating the Earth’s climate and because global climate has undergone major changes during this time period. However, current understanding of the EEP paleoceanography encounters two basic problems. First, this region is characterized by steep east-west and meridional gradients in Sea Surface Temperatures (SSTs) and biological productivity, which can vary from one year to another. Second, the seafloor lies below the lysocline in most of the area, leading to poor preservation of biogenic carbonate. As a result, sediments from the EEP exhibit major changes in their physical and compositional properties over short time, and hence sediment depth, increments. Therefore, the study of bulk sediment properties is crucial to further understand the paleoceanography of EEP during the past 8 Myr. Bulk sediment properties are highly appropriate proxies for achieving highly resolved and time comparable SST and biological productivity data because changes in such properties can be traced across the EEP over large distances.This thesis presents two manuscripts. In Paper 1 we examine the positive second-order relationship between wet bulk density (WBD) and carbonate content of sediments from the EEP. This relationship is important because it can be used to determine high-resolution carbonate content records. In Paper 2 we examine bulk sediment stable isotopes records from the EEP to understand what these records actually represent and whether these records are robust across the EEP. The main conclusions of these studies are (1) a single two-component equation cannot be used to determine carbonate content from the WBD. Instead, the WBD-carbonate relationship can only be described by an infinite series of curves representing the mixing of different components; (2) bulk sediment stable isotope records are robust across the EEP and changes in grain-size are not the primary cause of variations of these records.
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