| 1. |
- Schmidt, Manuela
(författare)
-
Persons who frequently use psychiatric emergency services : perspectives on who they are, what their needs are and howthey are encountered by healthcare professionals
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall objective of the thesis was to describe who persons that frequently use psychiatric emergency services (PES) in Sweden are, to explore what needs they experience as well as how healthcare professionals working at PES view the needs of those persons and experience encounters with them.This thesis includes both quantitative (I, II) and qualitative (II, III, IV) research designs and applies a broad range of data collection methods, such as use of register data (I), use of survey data (II), individual interviews and focus group interviews (III, IV). Data were analysed with statistical tests (I, II) and with qualitative content analysis (II, III, IV).Study I is based on visits to PES during 2013–2015. A total of 27,282 persons made 67,031 visits. Of those 27,282 persons, 8.1% could be identified as frequent PES users, accounting for nearly two fifths of all visits. In Study II, 81 persons who frequently visited PES participated. The participants in Studies III and IV were healthcare professionals working at PES, such as assistant nurses, nurses with specialised education in psychiatry, and physicians. Nineteen healthcare professionals participated in individual interviews in both Study III and Study IV, and each of the studies was complemented with a focus group interview involving five and six professionals respectively.The findings of this thesis were as follows: persons who frequently use PES in Sweden are a small, yet highly heterogeneous group who make a disproportionately high number of visits and differ significantly from other PES visitors; persons who frequently use PES and healthcare professionals at PES are in agreement about the complex and intertwined need patterns of the patients that originate from problems in everyday living, acute psychiatric suffering, and insufficient care possibilities, and thus were found to suffer from illness, unfavourable life circumstances and inadequate care; healthcare professionals at PES experienced the encounter as consisting of caring, professional, and humane processes where persons who frequently use PES were seen as fellow human beings and as unique, and were treated with as much respect, kindness, humility, confirmation, and empowerment as possible; and that in order to have caring encounters with persons who frequently use PES, the healthcare professionals also needed to nurture the relationship with oneself and with colleagues. Those results were interpreted by means of person-centredness and in light of a recovery-oriented care approach. Even though the latter has received more acknowledgement and acceptance within psychiatric care in the last decade, it needs to be developed and implemented further in the Swedish psychiatric care context.
|
|
| 2. |
- Deyhle Jr, Richard
(författare)
-
Cross-modal Imaging in Lung Research: From µCT dosimetry to synchrotron phase contrast microtomography biomechanical insights in preclinical lung injury models
- 2024
-
Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lung diseases continue to present a large burden to public health, especially in industrialized countries. For abetter understanding of the underlying patho-mechanisms in lung related diseases as well as for testing theefficacy of novel therapies, preclinical studies in animal models are indispensable. The significance of preclinical X-ray based micro-computed tomography (µCT) research lies in its ability to provide high-resolution, non-invasive lung imaging of small animals as the air inside the lung acts as a natural contrast and to image the lung parenchyma longitudinally to assess functional and morphological alterations and test efficacy of therapeutic interventions. This often requires requires imaging protocols that balance between sufficient image quality and clinically relevant radiation absorbed doses. A reproducible method for evaluation of absorbed radiation absorbed doses is desirable. Absorbed radiation absorbed doses were measured in a polymethyl methacrylate (PMMA) phantom using standard TLD and a novel type of OSLD made form household salt. Four imaging protocols from MILabs “xUHR-µCT” scanner were tested. A large discrepancy was observed from results compared to vendor-provided values. The results indicate a need for thorough empirical dose measurements prior to performing longitudinal studies. Four-dimensional imaging, allows for investigation of the dynamics of regional lung functional parameters simultaneously with structural deformation of the lung as a function of time. It is of significant interest to have direct visualization and quantification of interstitial lung diseases at spatial resolutions beyond the capabilities of clinical and conventional absorption-based only CT. Thus far, the high intensity of synchrotron X-ray light sources offer a tool to investigate dynamic morphological and mechanistic features, enabling dynamic in-vivo microscopy. This investigation elucidates the direct effects of interventions targeting the pathophysiology of Acute Respiratory Distress Syndrome (ARDS) and Ventilator-Induced Lung Injury (VILI) on the terminal airways and alveolar microstructure within intact lungs. In such conditions, the relationship between microscopic strain within the mechanics of the alveolar structure and the broader mechanical characteristics and viscoelastic properties of the lungs remains poorly understood. A time-resolved synchrotron phase-contrast micro-computed tomography imaging acquisition protocol based on the synchronization between the mechanical ventilation and the cardiac activity was used to resolve the lung parenchyma motion with an effective isotropic voxel size of 6 µm. Quantitative maps of microscopic local lung tissue strain within aerated lung alveolar tissue under protective mechanical ventilation in anesthetized rats were obtained. This approach was used to assess the effect of alterations in lung tissue biomechanics induced by lung injury at 7 days after single-dose, intratracheal bleomycin instillation in combination with short-term high-tidal volume (VT) mechanical ventilation. Overall, this work address the aspects of radiation exposure to in experimental imaging of small animals and lays a foundation for a more nuanced understanding of lung injury and mechanical ventilation. In the future, it may result in a more effective and less injurious respiratory support for patients with acute lung injury or chronic lung diseases.
|
|
| 3. |
- Kjellbom, Albin
(författare)
-
Autonomous cortisol secretion – Mortality, morbidity and diagnostics
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ContextUp to half of patients with adrenal adenomas found as incidentalomas show biochemical signs of subtle cortisol hypersecretion without having clinical signs or symptoms of Cushing’s syndrome. A condition called autonomous cortisol secretion (ACS). Previous studies have indicated that ACS might be associated with increased mortality.ObjectivesExplore if ACS is an independent risk factor for increased mortality. Evaluate low ACTH as a diagnostic marker of ACS. Investigate the prevalence of smoking in patients with adrenal adenomas.MethodsCohort and cross-sectional studies. Adult patients referred to two Swedish endocrine centres because of an adrenal adenoma, found as an incidentaloma, between 2005 and 2015 were enrolled. Mortality data were obtained from the Cause of Death Register. Patients were grouped according to predefined levels of cortisol after a 1-mg dexamethasone suppression test (cortisolDST); non-functional adrenal adenoma (NFAA), defined as cortisolDST Results1048 patients were followed for 6.4 years. Compared with NFAA mortality was not increased in cortisolDST 50-82 nmol/L, hazard ratio (HR) 1.17 (95% CI, 0.79-1.73)), while cortisolDST 83-137 and ≥138 nmol/L were associated with a significant increase in mortality, HR 2.33 (1.53-3.53) and 2.87 (1.74-4.74). Mortality did not differ significantly between 632 patients with NFAA and matched controls (3:1) when followed for 6.6 years, HR 1.13 (0.87-1.46). Studying 198 patients with unilateral adrenal adenomas and 100 healthy controls, low ACTH (ConclusionsACS is an independent risk factor for increased mortality, while NFAAs do not pose a relevant risk. The risk associated with ACS seems to become clinically relevant when the cortisolDST level is ≥83 nmol/L. Low ACTH is of limited value in diagnosing ACS, in part due to its high prevalence in patients with NFAA. Additionally, there appears to be a link between smoking, adrenal adenomas, and ACS.
|
|
| 4. |
- Schmidt, Tobias
(författare)
-
Monocytes and Neutrophils in Juvenile Idiopathic Arthritis
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Juvenile idiopathic arthritis (JIA) is a heterogenous inflammatory joint disease and the most commonrheumatic disease in children. Oligoarticular JIA (oJIA) is the major subgroup, which mainly affects fewand large joints, such as the knee. The immunological processes and key players driving inflammationwithin the affected joints are not well characterised. Research has primarily focused on adaptiveimmunity, and little is known of the contribution of the innate immune system. Neutrophils and monocytesare central members, with crucial roles as phagocytes, cytokine producers and regulators ofinflammation. Given the limited knowledge of the role of innate immunity in oJIA, we aimed tocharacterize the phenotype and function of monocytes and neutrophils in the arthritic joint.We found that synovial monocytes had both regulatory and pro-inflammatory features. For example, atthe surface level, they expressed markers of clearance and antigen presentation. This wascorrespondingly reflected at the mRNA level. Functionally, the synovial monocytes showed resistance tocytokine production upon further activation and had an increased efferocytosis. Additionally, they alsopromoted activation of healthy T-cells. Interestingly, we found that healthy monocytes acquired theregulatory features of synovial monocytes (both phenotypical- and fucntional features) through exposureto patient synovial fluid. This was primarily through the IL-6/JAK/STAT pathway. Furthermore, we showedthat the monocytes obtained the inflammatory features through cell-cell interactions, such as the abilityto promote T-cell activation. Specifically, we found that synovial fibroblasts induced this activation inhealthy monocytes in co-cultures in a contact-dependent manner, especially if the synovial fibroblastswere priorly exposed to synovial fluid. Indeed, this exposure to synovial fluid resulted in cytokineproduction and an enhanced ability to induce immune cell chemotaxis by the fibroblasts.Furthermore, we found that synovial neutrophils displayed signs of activation at the surface level, andthey had acquired a monocyte-like phenotype. This phenotype correlated with impaired effectorfunctions, primarily decreased phagocytosis ability and reactive oxygen species production. Interestingly,their phenotype could not be induced by stimulation of healthy neutrophils with synovial fluid, nor in cocultureswith synovial fibroblasts, suggesting that different mechanisms drive the neutrophil phenotype.Taken together, the results of this thesis describe the phenotype and role of synovial monocytes andneutrophils in the pathogenesis of oJIA, and emphasize potential underlying mechanisms driving theirphenotypes that could be utilized to develop therapies.
|
|
| 5. |
|
|
| 6. |
- Rydelius, Anna
(författare)
-
Brain Tumor Imaging and Treatment Effects. Imaging findings and cognitive function in glioblastoma patients.
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- AbstractBackground: Glioblastoma is the most common malignant brain tumor. Operation with maximal resection, if feasible, otherwise biopsy followed by radiotherapy and chemotherapy with temozolomide is standard therapy. The prognosis remains poor, with median overall survival being 15 months despite therapy. Improved monitoring and treatment response assessment will be important when seeking to improve treatment efficacy and patient quality of life.Aims: The present work sought to follow newly diagnosed glioblastoma patients by imaging and clinical monitoring. Specific aims were to study the impact of surgical resection degree on prognosis and the effects of currently used therapies, including arc-based rotation radiotherapy, longitudinally. Aims were also to study radiological parameters with advanced magnetic resonance imaging (MRI) as well as patient neurological and cognitive functions in order to early identify prognostic factors. Material and methods: In paper I, volumetric assessment by quantitative and subjective methods was retrospectively studied from pre- and postoperative MRI in glioblastoma patients undergoing tumor resection. Influence of extent of resection of contrast enhanced tumor on progression-free survival and overall survival was analyzed, measured as relative extent of resection (EOR) and absolute residual tumor volume (RTV). In the present MRI brain tumor study, patients newly diagnosed with glioblastoma undergoing treatment with arc-based radiotherapy were studied longitudinally over a one-year period and constituted the patient cohort of papers II-IV, using advanced MRI, including diffusion-weighted imaging sequences. Microstructural changes in non-tumorous brain structures, including white matter (corpus callosum, centrum semiovale) and the limbic system (hippocampus, amygdala), were assessed by diffusion tensor imaging (DTI) during and after irradiation. By parametric response mapping (PRM) changes of mean diffusivity (MD) in tumor regions were analyzed as MD-PRM. Baseline examinations were compared with examinations 3 weeks into radiotherapy voxel-wise, analyzing the MD-difference as prediction of therapy response and survival. Clinical parameters were monitored from start of radiotherapy up to one year and included correlation of cognition, measured by the computerized test-battery CNS-vital signs (CNS-VS), with therapy and disease progression.Results: Quantitative volumetric measurements, especially residual tumor volume of ≤1,6 mL, showed prognostic significance for longer progression-free and overall survival. The quantitative volumetric method was superior in reproducibility compared to conventional estimation. MD-PRM demonstrated that in patients only undergoing diagnostic biopsy MD-PRM, changes indicated prognostic specificity for treatment response at 8 months. Significant longitudinal DTI changes were only observed in the body of the corpus callosum during and up to one year from radiotherapy. Evaluation of cognitive performance in glioblastoma patients using cognitive test scores by CNS-VS at baseline were in lower-average or low, compared to standard test average in 4 main domains: executive function, visual and verbal memory and complex attention. Cognitive function remained stable without further deterioration during one year follow up after radiotherapy was initiated. Better cognitive function at therapy begin correlated with longer progression-free and overall survival. Conclusion: Quantitative volumetric assessment has prognostic impact on glioblastoma patients progression-free and overall survival in favor of gross total resection. MD-PRM could not predict treatment response as assessed in the entire patient cohort, but may have predictive value in biopsied patients. Longitudinal monitoring up to one year after initiated radiotherapy did not reveal any major changes, neither in microstructural changes by diffusion tensor imaging (DTI) parameters, nor in patients cognitive function, indicating less neurotoxicity by arc-based radiotherapy.
|
|
| 7. |
- Vansarla, Goutham
(författare)
-
Role of HAMLET and metabolism in treatment and pathogenesis of pneumococci
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antimicrobial resistance (AMR) is one of the principle public health problems in the 21st century, threatening the available treatment strategies for bacterial infections. Here, we present a human protein-lipid complex, HAMLET (human alpha-lactalbumin made lethal to tumor cells) purified from human milk as a potential therapeutic agent which has both tumoricidal and bactericidal activity. HAMLET’s anti-bacterial activity is selective, against respiratory pathogens with highest activity seen in Streptococcus pneumoniae (the pneumococcus). HAMLET-induced bacterial death was shown to require membrane depolarization and rupture by a sodium-dependent influx of calcium, interference with glycolysis and activation of kinases. In this thesis, to understand the role of HAMLET as a future therapeutic agent, we studied HAMLET-induced targets and pathways involved in pneumococcal death and host immunomodulatory effects, which can provide us with information about future potential bacterial targets and alternative treatment strategies. Additionally, to understand pneumococcal pathogenesis, we studied metabolism and biofilm formation in pneumococci with different niche-associated sugars (like galactose). In paper I, we observed that HAMLET results in inhibition of glycolysis and energy production in the cells. In paper II, we studied the interaction between HAMLET’s bacterial targets and observed that pneumococcal targets of HAMLET are either directly or indirectly related. In paper III, we observed that HAMLET induces immunomodulatory effects resulting in functional changes of monocyte-derived macrophages and dendritic cells. In paper IV, we observed that pneumococci grow slower and are less metabolically active in both planktonic and biofilm bacteria in the presence of galactose compared to glucose. Further, we show that galactose-grown bacteria disperse (spread) less in response to febrile temperature compared to glucose-grown bacteria. Overall, the results from this thesis suggest that HAMLET has dual anti-bacterial roles: first by directly killing bacteria and second by stimulating immune responses to eliminate bacteria. Additionally, in the presence of galactose pneumococcal growth and metabolism is slow, suggesting a role in bacterial pathogenesis (in vitro).
|
|
| 8. |
|
|
| 9. |
- Abdulrasak, Mohammed
(författare)
-
EVAR of AAA: Long term outcomes, disease progression and risk stratification
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundEndovasvular aortic repair (EVAR) is the most commonly utilised technique for the treatment of abdominal aorticaneurysms (AAA) in tertiary referral centers. Detailed long-term outcomes of this technique are relatively scarce,especially for patients presenting symptomatically with AAA. Intra-operatively, proximal type Ia endoleak, involvingblood circulating into the AAA – due to poor proximal seal of the endograft to the aortic neck region – is a fearedcomplication which is usually promptly treated, given its association with post-operative AAA expansion andrupture. Aneurysmatic disease is usually considered a progressive pathology with potential for progression toareas of the aorta beyond the known aneurysmatic segment. Arterial calcifications are established as a marker foratherosclerosis, yet the association of ilio-femoral calcification with post-operative mortality after EVAR is notknown.Aims1. Evaluate the long-term results of EVAR of AAA using a single endograft2. Compare the early and late results of EVAR of symptomatically presenting patients to those treated asymptomatically3. Study the long-term results of intra-operative treatment of type Ia endoleak using large, balloon expandable stents4. Study the progression of aortic disease for patients treated with endovascular means in the postoperative period5. Assess the novel ilio-femoral calcium score as a potential predictor for overall and cardiac-specific mortality after EVARResultsEVAR of AAA yields sustainable results in the long-term, for both symptomatic and asymptomatic patients. Thereis ≈ x4 elevated early mortality in symptomatic patients as compared to asymptomatic ones. Intra-operativetreatment of type Ia endoleaks using large, balloon-expandable stents should be reserved to patients treatedacutely with EVAR. Aortic expansion beyond the sealing zone is relatively uncommon, and seems related to theforce exerted on the aortic wall by the endograft. Ilio-femoral calcium score may predict long-term overall andcardiac mortality after EVAR, albeit the relation is weak. Therefore, further studies are needed to establish thisassociation.
|
|
| 10. |
- Abrahamsson, Johan
(författare)
-
Advanced Bladder Cancer. Aspects of Diagnosis and Treatment.
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Treatment of bladder cancer has seen few advancements in recent decades until the introduction of checkpoint inhibitors during the last few years. Bladder cancer diagnostics have been similarly impaired and the likely advent of novel treatments in the neoadjuvant setting will require new diagnostic tools in the preoperative setting in muscleinvasive bladder cancer.This thesis evaluates three diagnostic tools with a particular focus on guiding treament before or during neoadjuvant or induction chemotherapy. Firstly, we show that presence of a single CTC with CellSearch is associated with earlier progression in patients with advanced bladder cancer as well as metastatic disease on FDG-PET-CT. A significant proportion of bladder cancer cells express EpCAM and can be detected using EpCAM-antigen based methods.Secondly, in the setting of induction chemotherapy, complete metabolic response with FDG-PET-CT is associated with survival compared to a partial response during chemotherapy followed by radical cystectomy in patients with nodepositivebladder cancer. In a similar vein, we find that the CellSearch method is not feasible in monitoring chemosensitivity due to the low sensitivity of the method. Finally, bladder cancers of the luminal-like (GU- and Uro) subtypes display improved outcomes following cisplatin-based neoadjuvant chemotherapy compared to the Ba/Sqsubtype. The methods presented in this thesis are not mutually exclusive but rather constitute reciprocal biomarkers providing information about risk of occult metastatic disease, predicted and actual response to chemotherapy at time-points wheresuch information can be clinically useful. Novel neoadjuvant treatment options for bladder cancer will likely result in a renaissance in preoperative diagnostics as alternative treatments will allow for randomized study designs for biomarkers. Future diagnostic workups will likely entail an extended suite of such biomarkers and diagnostic tools to provide all aspects of a patient’s disease.
|
|
| 11. |
- Adrian, Gabriel
(författare)
-
Altering Radiation Response with Time, Volume and Fractionation
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Radioresistance, the failure to achieve a desired outcome, is an obstacle in clinical radiotherapy. In this thesis we investigate factors affecting radioresistance and strategies to overcome it, both with established clinical approaches and by using novel pre-clinical discoveries. Study I & II concern the impact of tumour volume in patients with oropharyngeal cancer. In a large, pooled cohort of 654 patients from three clinical trials, we show that tumour volume is the predominant factor for local control, progression free survival and overall survival. The negative impact of large tumour volumes could, in exploratory analyses, be mitigated by intensified radiotherapy. The studies also confirm the prognostic role of HPV/p16- associated tumours, haemoglobin level and smoking status. Based on the results, individualized treatment based on tumour volume could be suggested. The second part of the thesis is based on pre-clinical experiments of novel discoveries. FLASH, the use of ultra-high dose rate radiotherapy where the irradiation is delivered in a fraction of a second, has been shown to spare normal tissue without hampering tumour control. Thereby, FLASH could be used to overcome radioresistance by escalating the dose to the tumour without increasing the risk of normal tissue complications. Oxygen has been proposed to play a key role in mediating the FLASH effect. We investigated the role of oxygen concentrations in a prostate cancer cell line and found that the FLASH effect appeared in hypoxic cells, but not in normoxic (study III). To further elucidate if FLASH effects are solely appearing in hypoxia, we investigated six additional cell lines under normoxic conditions and found that a FLASH effect may also appear in normoxia (study IV). We did not find any correlation between the FLASH effect and induction of DNA double strand breaks or cell cycle arrests. In the last two decades the discovery of bystander and rescue effects has broaden the understanding of radiation responses. Not only directly hit cells are affected by the irradiation, and cellular communications contribute to part of the radiation response. We investigated if cellular communications could induce radioresistance. By varying the number of irradiated cells, adding cell conditioned medium and irradiating only half of the cells, we found that cellular communications cause a rescue effect, hence radioresistance. In summary, the thesis underpins that radiation responses can be altered. To overcome radioresistance due to large tumour volumes, intensified radiotherapy for patients with large oropharyngeal cancers should be considered. The clinical exploitations of FLASH and bystander/rescue effects remain to be investigated.
|
|
| 12. |
- Adrian, Maria
(författare)
-
Central venous catheterisation - clinical studies on mechanical complications in the ultrasound-guided era
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Central venous catheterisation is one of the most common invasive procedures performed on patients in secondary care. Unfortunately the catheterisation procedure is associated with mechanical complications that both can be life-threatening and may force postponement of life-saving treatments such as surgery and chemotherapy. The use of real-time ultrasound guidance increases success rates and reduces the numbers of mechanical complications - but major mechanical complications still occur. The general aim of this thesis was to explore various aspects of ultrasound-guided central venous catheterisation and associated mechanical complications in order to enable future quality improvements of the procedure.Papers I and II investigate the incidence of mechanical complications within 24 hours after central venous catheterisation and analyse possible associated risk factors. In total, 12 667 central venous catheter insertions in 8 586 patients were included. We found that in hospitals where real-time ultrasound guidance is standard of care for central venous access, the incidence of major mechanical complications was only 0.4%. We also identified patient BMI <20 kg/m2, male operator gender, limited operator experience and more than one skin puncture as independent risk factors for major mechanical complications. In addition, subclavian vein catheterisation was an independent risk factor for pneumothorax compared to internal jugular vein catheterisation. Paper III evaluates the use of a micro-convex probe and the right supraclavicular fossa ultrasound view for aiding guidewire positioning to avoid catheter misplacements in right infraclavicular subclavian vein catheterisation. We prospectively included 103 patients and showed that with the ultrasound method described, 14 of the 15 initially misplaced guidewires were detected and 12 of them were successfully adjusted to a correct position, which in turn helped avoid 12 catheter misplacements at the time of insertion. Paper IV estimates the minimal guidewire length required to avoid guidewire retraction, thereby maintaining a guidewire tip position in the lower segment of the superior vena cava throughout an ultrasound-guided infraclavicular catheter placement in the right subclavian vein. Based on vessel measurements in 100 patients, we concluded that the majority of the assessed 15–16 cm central venous catheter kits contain guidewires that are too short for right subclavian vein catheterisation, i.e., guidewire retraction is needed prior to catheter insertion. Paper V examines the effect of an implementation package on the documentation of central venous catheter insertions. We found that introduction of an updated central venous catheter insertion form, delegated information responsibility of the new local directions for central venous catheter placement, and follow-up of all registered insertion forms during a limited period of time reduced the porportion of missing data with 55%.The general conclusion of this thesis is that there are possibilities for further quality improvements of central venous catheterisation also in the ultrasound-guided era and that the combination of appropriate recording of central venous catheter insertions, possibilities to track patient outcomes, and clinical research contribute to advanced understanding and delivering of patient-safe healthcare.
|
|
| 13. |
- Afua Quaye, Angela
(författare)
-
The Child's Best Interests during Hospitalisation - What does it imply?
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionThe child’s best interest has moral foundations in medicine and has existed for decades in the field of paediatrics. Indeed, there are recommendations for the child’s best interests to be a primary consideration in all matters that concern the child. However, there is uncertainty in the literature over how the child’s best interests may be safeguarded within healthcare. AimThe aim of this thesis was to elucidate from various perspectives, the experiences of the child’s best interests during hospitalisation.MethodsA naturalistic paradigm was used, employing qualitative exploratory and qualitative descriptive designs. Data were collected from paediatic units in Sweden and Australia. Thirty-two observations of the interactions between children, their parents and healthcare professionals were graded using the Scale of Degrees of Self-Determination and normative assessments. The same 32 observations were also analysed using inductive content analysis and abductive reasoning. Further, inductive thematic analysis of interviews with nine children, and inductive content analysis of interviews with 16 parents was conducted. ResultsThe findings show that interpersonal relationships, an enhancing environment, effective communication, mutual negotiations and collaborations, and active participation are essential to safeguarding the child’s best interests during hospitalisation.ConclusionThe factors involved in safeguarding the child’s best interests during hospitalisation are interconnected and nested in a rather complex system and can be further understood using Bronfenbrenner’s bioecological model. The child’s best interests are context-dependent, situational, flexible, and dependent on all actors involved and actual decisions made. Safeguarding the child’s best interests during hospitalisation requires a case-by-case approach and a holistic view of the child, beyond their clinical treatment.
|
|
| 14. |
- Agger, Erik
(författare)
-
Factors predicting recurrence in rectal cancer
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Rectal cancer treatment has improved through important incremental surgical and oncological developments over the past decades. Localized disease is highly treatable with multimodal surgical and oncological therapy. Prognosis is dependent on several factors with tumour stage at diagnosis being the most important. Furthermore, curative treatment is highly dependent on radical surgical resection. Positive circumferential resection margin (CRM), lateral lymph node metastases and tumour deposits are examples of high-risk clinical situations associated with increased risk of recurrence and subsequently impaired long-term outcome and are investigated in this thesis.Aims: Paper I & II, to investigate CRM-positive resections in rectal cancer and effect on local recurrence and distant metastasis risk. Paper III, to describe MRI-positive lateral lymph nodes – investigating therapy and outcome in high-risk rectal cancer. Paper IV, to investigate the prognostic significance of tumour deposits as a risk factor and in comparison with lymph node involvement in rectal cancer.Method: Paper I-II & IV are retrospective national cohort studies. Paper III is a retrospective regional cohort study. Patient data was gathered from the Swedish ColoRectal Cancer Registry, medical records and the Swedish Cause of Death registry. Patients for paper I & II were between 2005 – 2013, for paper III between 2009 – 2014 and för paper IV between 2011 – 2014.Main outcome measures: Paper I, local recurrence. Paper II, distant metastasis. Paper III, descriptive tumour characteristics, overall survival, local recurrence and distant metastasis. Paper IV, local recurrence, distant metastasis, overall and relative survival.Results and conclusions: Exact CRM was associated with increased local recurrence risk. Neoadjuvant radiotherapy does not decrease risk of local recurrence in CRM-positive patients. Only a subset of patients with R1-resection (CRM 0.0 mm) suffered local recurrence during follow-up. Exact CRM equal to or less than 1.0 mm may be a risk factor for distant metastasis. However, several other factors likely contribute to increased risk of distant metastasis in CRM-positive patients. MRI-positive lateral lymph nodes were associated with synchrounous distant metastasis. Neoadjuvant (chemo)radiotherapy, abdominal rectal resection and selective lymph node dissection may be a useful approach in patients with MRI-positive lateral lymph nodes. Tumour deposits increased risk of both local recurrence and distant metastasis and decreased survival. The prognosis of patients with tumour deposits were comparable to pN1a-b stage mesorectal lymph node involvement.
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
- Aidoukovitch, Alexandra
(författare)
-
Saliva: a cell suspension of epithelial cells harboring the antimicrobial peptide LL-37 and the growth factor EGF
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Saliva plays a crucial role in maintaining oral health through its physical and chemical properties that provide various protective functions. One of its essential components is the human host defense peptide LL-37, which is produced by immune cells and epithelial cells, and participates in the first line of defense against pathogens. LL-37 is a potent antimicrobial agent against both gram-positive and gram-negative bacteria, and furthermore it also modulates immune responses. Another important component of saliva is epidermal growth factor (EGF), which is produced by different cell types and acts as an essential stimulus of epithelial cell proliferation and differentiation, in wound healing and tissue repair. The levels of these peptides may be affected by various oral diseases. For instance, in periodontal disease, alterations in LL-37 and EGF contents and function have been observed in response to inflammation. The objective of the present doctoral thesis was to provide added information and insights into the salivary components LL-37 and EGF, and their functional importance by studying isolated human saliva from the major salivary glands, whole saliva, salivary glandular tissues, and cells in whole saliva. Multiple analyzing methods were used to quantify and visualize protein levels and cellular distribution of the peptides. The results demonstrated that all three major human salivary glands contributed to salivary hCAP18/LL-37 content of whole saliva, and immunohistochemistry applying co-localization analysis revealed that salivary hCAP18/LL-37 appears to originate from intravascular neutrophils. Furthermore, ELISA analysis showed that hCAP18/LL-37 was observed in both the cell-free and cell-containing proportions of human whole saliva, arguing that salivary cells also carry the peptide. Desquamated salivary epithelial cells expressed both hCAP18/LL-37 and EGF, proposing that these cells harbor both peptides and implying that the cells might play a prominent role in the innate immune response. The cells spontaneously released/leaked LL-37 into the extracellular medium, although its endogenous levels were too low to have an impact on S. mutans viability. Moreover, the findings revealed that whole saliva and cell-free saliva from caries-active subjects 18-23 years old contained similar amounts of hCAP18/LL-37 in comparison to controls. Interestingly, caries-active subjects with gingivitis displayed higher concentrations of hCAP18/LL-37 compared to caries-active subjects without gingivitis. In gingivitis, neutrophils are found in saliva, and since these cells are rich in hCAP18/LL-37, they probably contribute to the high levels of hCAP18/LL-37 found in saliva of these subjects. In conclusion, this thesis provides new knowledge and insights into the origin and function of hCAP18/LL-37 in human saliva, especially its distribution in different fractions of saliva, and the salivary concentration of hCAP18/LL-37 in subjects with dental caries and gingivitis. Moreover, we propose a novel functional importance of desquamated oral epithelial cells as carriers of hCAP18/LL-37 and EGF.
|
|
| 19. |
- Aked, Joseph
(författare)
-
Stroke Epidemiology and Outcome in Southern Sweden
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Stroke is a common cause of mortality and disability worldwide and continuously updated, thorough information of itsoccurrence and outcome is needed. In recent years, multiple advances have been made in stroke prevention and treatment that mayhave changed the epidemiology and outcome of stroke.Aims: To investigate updated population-based stroke epidemiology as well as long-term survival, recurrence and functional outcomein southern Sweden.Methods: Paper I: A population-based cohort of 413 consecutive patients with first-ever stroke in 2015-2016 was assembled usingthe prospective hospital-based stroke studies Lund Stroke Register (LSR) and Riksstroke, as well as retrospective searches ofprimary care, outpatient clinic and autopsy sources. Age- and sex-standardized incidence rates were calculated and compared with aprior study from the same study area in 2001-2002.Paper II: A subset of the population-based cohort of 400 patients (only ischemic stroke and intracerebral hemorrhage) was comparedwith LSR and Riksstroke regarding case ascertainment and which patients were not included in the hospital-based stroke studies.Paper III: The 400 individuals in the population-based cohort were followed up after 3 years regarding survival and causes of deathby using the Swedish Causes of Death Register, and stroke recurrence by using medical record review. Index and recurrent strokeswere classified by pathogenetic mechanism using the TOAST classification. Stroke survival at 3 years was compared with priorstudies in our area from 1983-1985, 1993-1995, and 2001-2002.Paper IV: The population-based cohort was followed-up in-person or via telephone at 3-4 years regarding functional outcome (mRS),dependency in activities of daily living (ADL), and health-related quality of life (HRQoL). Data were also collected on potentiallycorrelated health problems after stroke such as fatigue, cognitive impairment and depression.Results: Paper I: The total population-based age- and sex-standardized rate of stroke incidence was 165 per 100 000 person yearsin our study area, a 33% decrease compared with a population-based study in our area from 2001-2002. However, stroke incidencerates did not change for hemorrhagic stroke or among those <65 years.Paper II: LSR detected 363 (91%) of cases while Riksstroke detected 328 (82%). Patients undetected by the hospital-based studieshad high case fatality (44% vs 9%; p=0.001), and those only detected in primary care (n=11) often lived in nursing homes (57%).Those not detected by Riksstroke had less severe stroke (median NIHSS 3 vs 5; p=0.013).Paper III: In total, 265 (66%) survived 3 years after first-ever stroke. Among individuals with ischemic stroke, cardio-aortic embolismas pathogenetic mechanism was associated with the lowest 3-year survival (51/91; 56%). Cardiovascular disease was the cause ofdeath in 59% of cases (79/135). Meanwhile, 8% (32/400) had a recurrent stroke within 3 years, and the pathogenetic mechanism ofischemic stroke changed between first-ever stroke and recurrence in 16/29 (55%) cases. Three-year survival improved between the1980s and the present study (56% vs 66%; p=0.002), but survival did not change significantly between the early 2000s and thepresent study (64% vs 66%; p=0.48. Paper IV: In all, 202 individuals were clinically followed-up after a median of 3.2 years, while 47(12%) stroke survivors were lost to follow-up. Among followed-up survivors, 147 (73%) had favorable functional outcome (mRS≤2)and 134 (69%) reported good-excellent HRQoL. Age, stroke severity, professional care pre-stroke and recurrent stroke (all p<0.001)were predictors of poor functional outcome. Among follow-up variables, fatigue (p=0.001), and stroke severity (p<0.001) wereassociated with dependency in ADL, and fatigue (p<0.001) was also associated with worse HRQoL.Conclusions: Stroke incidence and survival have improved over recent decades, however some subgroups of stroke have notimproved in the same manner. Thorough population-based epidemiological studies of stroke are important to avoid and to possibleselection bias in hospital-based stroke studies. Around 3 of 10 long-term stroke survivors have poor outcome, and fatigue may be asignificant contributor to post-stroke function and health.
|
|
| 20. |
|
|
| 21. |
- Al-Mashat, Mariam
(författare)
-
Assessment of Pulmonary Blood Flow in Heart Failure. Using Novel and Non-Invasive Diagnostic Methods.
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In heart failure (HF), the heart is unable to pump effectively in order to satisfy the demands of the body. The elevated filling pressure seen in HF leads to accumulation of fluid in the lungs, i.e pulmonary congestion. While investigation with chest X-ray is recommended, it has limitations in detecting pulmonary congestion. Ventilation/perfusion single-photon emission computed tomography (V/P SPECT), i.e tomographic lung scintigraphy, is a promising method to diagnose and quantify pulmonary congestion in HF but needs to be validated by invasive right-heart catheterization. The variation of the blood volume in the pulmonary circulation measured by magnetic resonance imaging (MRI) may also have the potential to quantify the severity of HF.The general aim of this thesis was to develop and validate new non-invasive methods to diagnose and quantify pulmonary congestion and variation of the pulmonary blood flow in patients with HF, as well as to follow-uppulmonary congestion.Paper I revealed that the degree of pulmonary congestion in HF could be diagnosed and quantified using V/P SPECT. It was validated with right-heart catheterization. V/P SPECT was more accurate than chest X-ray in diagnosing pulmonary congestion in HF.In Paper II V/P SPECT showed that the pulmonary perfusion pattern was improved and that V/P SPECT could be used to follow treatment effect after heart transplantation in patients with HF and quantify the degree of pulmonarycongestion. It was validated with right-heart catheterization.Paper III demonstrated that V/P SPECT could be used to follow treatment effect and assess the degree of pulmonary congestion in patients with HF after receiving cardiac resynchronization therapy (CRT). V/P SPECT was associated with improvement in patients’ symptoms.Paper IV showed that the pulmonary blood volume variation differed between patients with HF and healthy controls. In patients with HF, approximately 40% of the variation could be explained by the left ventricular longitudinal contribution to stroke volume and the phase shift between the in- and outflow to the pulmonary circulation. The remaining variation (60%) likely occur on a small vessel level.In summary, pulmonary congestion in HF is difficult to quantify objectively. The non-invasive methods V/P SPECT and MRI might add complementary information in the diagnosis of HF. V/P SPECT can be used to follow treatment effects after heart transplantation and CRT and may have a role in avoiding invasive right-heart catheterization in selected cases and aid in treatment decision.
|
|
| 22. |
- Alamiri, Feiruz
(författare)
-
Antibiotic resistance and pathogenesis of Streptococci with focus on Group A Streptococci
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multi-drug resistant (MDR) infections remain the leading cause of death worldwide. MDR infections caused by Streptococcus pneumoniae (Spn), Streptococcus pyogenes (GAS) and Streptococcus agalactiae (GBS) are considered global threats to human health due to increased spread of antibiotic resistance and limited treatment options. In this thesis, we present the human milk derived HAMLET (Human Alpha-lactalbumin Made Lethal to Tumor cells) complex as a potential therapeutic alternative against streptococcal infections for its bactericidal and bacteriostatic activity against broth grown streptococci (Spn, GAS, or GBS). Adding to it, HAMLET potentiated antibiotic activity that renders antibiotic-resistant streptococci sensitive to the drugs they are resistant to, regardless of expressed serotype or antibiotic-resistance mechanism (target modification or efflux pumps). Biofilm formation and intracellular residence are antimicrobial avoidance mechanisms that help GAS escape host- or antibiotic-killing mechanisms. After completed antibiotic treatment against pharyngitis, intracellular bacteria may re-emerge and cause recurrent infections, leading to treatment failure. This thesis aims to identify novel therapeutic targets during respiratory infections by investigating GAS mediated pathogenic mechanisms. As most biofilms were studied on non-representative abiotic surfaces, we used a well-established biofilm model mimicking the respiratory niche to show that biofilm formation on pre-fixed epithelial cells is common in GAS. Proteome analysis of biofilm bacteria helped us identify proteins involved during biofilm formation and show that highly down-regulated protein expression is needed to form highly functional biofilms. In a live cell infection model, we show that biofilm bacteria internalize and persist equally long among GAS strains within epithelial cells. Using these models along with GAS strains lacking or expressing known virulence factors, we identify the role of these factors during biofilm formation and uptake into respiratory epithelial cells by GAS.Overall, the results obtained here are of clinical importance and could help in finding potential therapeutic strategies targeting streptococci during respiratory infections.
|
|
| 23. |
- Alexandridis, Vasileios
(författare)
-
The use of implants in female pelvic floor reconstructive surgery. Short and long term efficacy and safety.
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pelvic floor reconstructive surgery (PFRS) has suffered from high recurrence rates ever since its birth. Implants were thus quickly employed, initially autologous grafts and allografts. Technological development led to the manufacturing of synthetic implants that were believed to provide the support needed during urinary incontinence and pelvic organ prolapse (POP) surgery. However, due to a surge of reported complications, the place of implants in PFRS remains the object of major debate. Evaluation of the long-term performance of the use of implants is critical, while efforts are made for the development of new techniques, like the single-incision slings (SIS), and new materials, like the porcine small intestinal submucosa graft (PSG).Study I is a three-year follow-up of a multicenter randomized controlled trial comparing the SIS Ajust® with conventional mid-urethral slings (MUS) for the treatment of stress urinary incontinence. Based on patient-reported outcomes, Ajust® is found to be equally effective and safe with MUS.Studies II and III utilize a register-based cohort of women to evaluate the long-term performance of MUS for the treatment of stress urinary incontinence. Ten years after surgery, MUS demonstrate good subjective results with a small decline in efficacy and acceptable complications profile. The retropubic approach displays higher long-term efficacy than the transobturator with no difference regarding safety. No difference is found between the two techniques for the application of MUS concerning dyspareunia or pelvic pain in a ten-year perspective.Study IV is a retrospective study examining the short-term complications and recurrence rates of POP surgery augmented with PSG. The relatively high recurrence rates do not suggest a clear benefit from PSG use, while pain and urinary tract symptoms hold a central position in the complications profile of PSG-augmented POP surgery.In conclusion, Ajust® appears to be equally effective and safe as MUS in a three-year setting. Retropubic slings show higher efficacy than transobturator at ten years while both techniques present good results with similar and acceptable profiles regarding complications, pain and sexual function. Finally, there are no clear benefits from the use of PSG in POP surgery.
|
|
| 24. |
- Algaber, Anwar
(författare)
-
MicroRNA-Mediated Migration of Colon Cancer Cells
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is the second most common cancer in women and third most common cancer in men worldwide. The cause of the majority of death related to CRC is believed to be the migration of cancer cells to distant organs which is known as cancer metastasis. The mechanism behind cancer cell metastasis is not fully understood but accumulating studies suggest that it could be due to enhanced tumor cell motility due to overexpression of metastasis related proteins. It is believed that microRNAs (miRNAs) play a significant role in the tumorigenesis and metastasis of cancer by regulating oncogenes. The aim of this thesis is to investigate the mechanism of miRNA-mediated colon cancer cell invasion and migration as well as possible targets genes of miRNAs. We found that knockdown of miR-155-5p by antagomiR reduces the expression of HuR mRNA and migration of colon cancer cells. Our data also showed that miR-155-5p is involved in positive regulation of HuR protein under stress conditions. Notably, this positive regulation is regulated by direct binding of miR-155-5p at AU rich element region in 3ʹ-UTR of HuR mRNA. In addition, it was found that miR-340-5p is also involved in colon cancer cell invasion and migration by regulating RhoA and FHL2 mRNA expression. Bioinformatics analysis revealed that both RhoA and FHL2 mature mRNA have conserved binding sites from 2 to 8 base positions for miR-340-5p. The seed region of miR-340-5p directly binds with the target sites of RhoA and FHL2 mRNA and negatively regulate their expression under stress conditions. We found that the inhibition of RhoA and FHL2 expression by the use of mimic miR-340-5p reduced colon cancer cells invasion and migration. In addition, it was found that inhibition of FHL2 reduces cancer cells proliferation and increases E-cadherin expression in colon cancer cells, suggesting that targeting FHL2 and RhoA by miR-340-5p might be a useful approach to antagonize colon cancer cells metastasis. The results of our studies not only show diverse mechanisms of colon cancer cells migration, but also provided valuable information that miRNAs can be an important target to develop new and effective therapeutics against colon cancer cells metastasis. Taken together, our data uncovered several new mechanisms for better understanding the mechanism of colon cancer cells metastasis and suggest that targeting miRNAs function could be a useful strategy to prevent colon cancer metastasis.
|
|
| 25. |
|
|
