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Sökning: WFRF:(Kjellman Magnus)

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2.
  • Chu, Xia, 1981- (författare)
  • Aspects of MEN1 Tumorigenesis in Endocrine Pancreas and Adrenal Glands
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Multiple endocrine neoplasia syndrome type 1 (MEN1) is an autosomal dominantly inherited disease, which is described as an association of tumors mainly in endocrine organs, including pancreas and adrenal glands. Pancreatic neuroendocrine tumors (PNETs) are the most common cause of death in MEN1 patients. More than one third of the MEN1 patients also develop enlargement of the adrenals. MEN1 is caused by a germline mutation of MEN1 gene, a tumor suppressor gene that is located on the human chromosome 11. As noticed, the MEN1 related tumors often develop prior to inactivation of both wild type alleles, indicating MEN1 haploinsufficiency. In this thesis, I utilized a conventional Men1 mouse model that has the phenotype mimicking the human MEN 1 traits, in order to investigate MEN1 tumorigenesis in endocrine pancreas and adrenal glands.  The microvascular aberrations contributing to development and maintenance of PNETs were characterized. The increased vascular density of PNETs developed in the Men1 mice was paralleled by an early and extensive redistribution of pericytes within endocrine tissue. These morphological alterations were supported by fine-tuned variations in expression of several angiogenic regulators  (VEGF, FGF and PDGF) and were further potentiated by hypoxia. Vascular reactivity and blood perfusion of tumor arterioles were significantly altered in response to glucose and L-nitro-arginine methyl ester.Investigation of adrenals from10-month-old Men1 mice showed 681 proteins in mass spectrometry data sets, in which 52 proteins were commonly found in the Men1+/+ and Men1+/- adrenals, and the differential expression between the genotypes reached significant levels. Prdx3, catalyzing the reduction of oxidative stress to cell survival, is one of the overexpressed proteins. Some proteins belonging to the PPARα pathway, e.g. ACLY were also overexpressed. Subsequent microRNA (miRNA) profiling analysis of adrenals from the same age group revealed 31 miRNAs whose expression was significantly altered in comparison between the genotypes. The tumor suppressor miRNAs, miR-486, miR-330 and miR-214, were significantly downregulated in Men1+/- adrenals. The latter, miR-214, is known to inhibit ACLY expression. This finding was in concordance with the proteomic analysis. The oncogene miRNAs, miR-132 and miR-494, were significantly enhanced in the Men1+/- adrenals. Gene ontology analysis demonstrated overrepresentation of the miRNA-targeted genes that are involved in nucleic acid metabolism, vasculature development, angiogenesis, and transcription. Together, these finding after validation in humans may be exploited to improve MEN1 cancer treatment.  
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  • Evertsson, Maria, et al. (författare)
  • Combined Magnetomotive ultrasound, PET/CT, and MR imaging of (68)Ga-labelled superparamagnetic iron oxide nanoparticles in rat sentinel lymph nodes in vivo
  • 2017
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Current methods for intra-surgical guidance to localize metastases at cancer surgery are based on radioactive tracers that cause logistical challenges. We propose the use of a novel ultrasound-based method, magnetomotive ultrasound (MMUS) imaging that employ a nanoparticle-based contrast agent that also may be used for pre-operative PET/MRI imaging. Since MMUS is radiation free, this eliminates the dependence between pre- and intra-operative imaging and the radiation exposure for the surgical staff. This study investigates a hypothetical clinical scenario of pre-operative PET imaging, combined with intra-operative MMUS imaging, implemented in a sentinel lymph node (SLN) rat model. At one-hour post injection of (68)Ga-labelled magnetic nanoparticles, six animals were imaged with combined PET/CT. After two or four days, the same animals were imaged with MMUS. In addition, ex-vivo MRI was used to evaluate the amount of nanoparticles in each single SLN. All SLNs were detectable by PET. Four out of six SLNs could be detected with MMUS, and for these MMUS and MRI measurements were in close agreement. The MRI measurements revealed that the two SLNs undetectable with MMUS contained the lowest nanoparticle concentrations. This study shows that MMUS can complement standard pre-operative imaging by providing bedside real-time images with high spatial resolution.
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  • Evertsson, Maria, et al. (författare)
  • In vivo magnetomotive ultrasound imaging of rat lymph nodes - a pilot study
  • 2015
  • Ingår i: 2015 IEEE International Ultrasonics Symposium (IUS). - 1948-5719.
  • Konferensbidrag (refereegranskat)abstract
    • The drive to gain a better understanding of how diseases arise and how to provide ever-earlier detection are some of the key factors for the development of molecular imaging. Compared to other imaging modalities ultrasound has not received the same attention for molecular imaging mainly due to its limited contrast resolution, together with contrast agents confined to the intravascular space. To overcome these issues, new nano-sized contrast agents and new ultrasound imaging techniques e.g. photo acoustic imaging, have been developed. Another such imaging technique under development is magnetomotive ultrasound imaging (MMUS). We have previously developed a frequency and phase tracking algorithm which is able to detect superparamagnetic iron oxide nanoparticles (SPIO NPs) using MMUS, where our suggested first clinical application is to detect sentinel lymph nodes (SLNs) in breast cancer surgery. Recently we have shown detection of SPIO laden rat SLNs in situ. Here we present the feasibility of in vivo detection of SLNs in rats. The algorithm clearly pinpoints the NP laden SLN, even in presence of significant artefactual tissue movement. The magnetomotive displacement increased when a higher voltage was applied on the coil creating the magnetic field (e.g. 56.6% increasing the voltage from 20V to 50V). An uneven concentration distribution of NPs in the SLN was found. The maximum magnetomotive displacement difference between two different cross sections in one SLN was 9.76 times. The study also showed that for a higher concentration of NPs a lower magnetic coil excitation voltage could be used in order to create a magnetomotive displacement of a certain magnitude. The result from this in vivo study shows that the method has potential for future clinical use.
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  • Evertsson, Maria, et al. (författare)
  • Magnetomotive Ultrasound Imaging Of Rat Lymph Nodes In Situ: Assessment Of Imaging Parameters
  • 2013
  • Ingår i: 2013 IEEE International Ultrasonics Symposium (IUS). - 9781467356855 ; , s. 600-603
  • Konferensbidrag (refereegranskat)abstract
    • Detection and removal sentinel lymph nodes (SLN) is important in the diagnosis and treatment of breast cancer and malignant melanoma. The SLN is the first regional lymph node draining the cancer tumor and if the cancer has spread it is most likely to find cancer cells in the SLN. In this study we have been able to detect multimodal superparamagnetic iron oxide nanoparticles (SPIO-NP) in rat SLNs in situ using magnetomotive ultrasound imaging (MMUS). In MMUS a time-varying external magnetic field acts to move the NPs and, thus, the NP-laden tissue. This movement can be detected by proper processing of ultrasound data. We have recently developed an MMUS algorithm, based on quadrature detection and phase gating at the frequency of NP displacement, and this is the first study where the algorithm is evaluated in animals. For both higher NP-concentration, as well as smaller NPs, we found that the MMUS data showed a larger displacement (1.56 +/- 0.43 and 1.94 +/- 0.54 times larger, respectively). The MMUS displacement also increased with a lower excitation frequency (1.95 +/- 0.64 times larger for 5 Hz compared to 15 Hz) and higher excitation voltage (2.95 +/- 1.44 times larger for 30V compared to 10V). The results from this study show that the MMUS technique has potential to be used as bedside guidance during SLN surgery, well as being used as standalone technique in a number of other applications such as stem cell tracking and cardiovascular research.
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8.
  • Evertsson, Maria, et al. (författare)
  • Multimodal Detection of Iron Oxide Nanoparticles in Rat Lymph Nodes Using Magnetomotive Ultrasound Imaging and Magnetic Resonance Imaging
  • 2014
  • Ingår i: IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. - 0885-3010. ; 61:8, s. 1276-1283
  • Tidskriftsartikel (refereegranskat)abstract
    • Detection and removal of sentinel lymph nodes (SLN) is important in the diagnosis and treatment of cancer. The SLN is the first regional lymph node draining the primary tumor, and if the cancer has spread, it is most likely to find metastases in the SLN. In this study, we have for the first time been able to image the very same contrast agent, superparamagnetic iron oxide nanoparticles (SPIO-NPs), in rat SLNs by using both our frequency-and phase-gated magnetomotive ultrasound (MMUS) algorithm and conventional magnetic resonance imaging (MRI); MMUS post mortem, MRI in vivo. For both higher NP-concentration and smaller NPs, we found that the MMUS data showed a larger magnetomotive displacement (1.56 +/- 0.43 and 1.94 +/- 0.54 times larger, respectively) and that the MR-images were affected to a higher degree. The MMUS displacement also increased with lower excitation frequency (1.95 +/- 0.64 times larger for 5 Hz compared with 15 Hz) and higher excitation voltage (2.95 +/- 1.44 times larger for 30 V compared with 10 V). The results show that MMUS has potential to be used as bedside guidance during SLN surgery, imaging the same particles that were used in prior staging with other imaging techniques.
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  • Fan, Xuelong, et al. (författare)
  • Ergonomic Evaluation of a Prototype Console for Robotic Surgeries via Simulations with Digital Human Manikins
  • 2019
  • Ingår i: Proceedings of the 20th Congress of the International Ergonomics Association (IEA 2018) Volume V: Human Simulation and Virtual Environments, Work With Computing Systems (WWCS), Process Control. - Cham : Springer International Publishing. - 2194-5365 .- 2194-5357. - 9783319960760 ; 822, s. 351-363
  • Konferensbidrag (refereegranskat)abstract
    • Work-related musculoskeletal disorders impact surgical performance, which increase risks for patient safety. A new console has been designed to reduce workload for robotic surgery surgeons. Due to high costs and long waiting time of the production process, a pre-production ergonomic evaluation of the new design is preferable. In this paper, we evaluate if the new console at the pre-production stage by using an US checklist, and the Swedish standard for visual display unit work. A 3D model of the new designed console was introduced to the virtual environment of a digital manikin (Intelligently Moving Manikin, IMMA). The work-ranges of the console were calculated. Various individual work distances of 12 manikins (3 men and 3 women per each of the US and the Swedish population) were “measured”. The data were integrated and used as an objective reference to compare with the Swedish standard, and the US checklist. The result shows that the criteria in the Swedish standard and the US checklist are fulfilled, except for those are related to the adjustable range of the screen view height, the height range of the armrest and the adjustable distance of the pedals. The new console fulfills most of the criteria in the checklist and the standard, but there is room for a few improvements. The DHM tool IMMA provides the possibility for a pre-production assessment. However, the limited virtual measurement tools of IMMA restrained the time efficiency of the ergonomic assessment.
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  • Fan, Xuelong, et al. (författare)
  • Ergonomics and performance of using prismatic loupes in simulated surgical tasks among surgeons – a randomized controlled, cross-over trial
  • 2023
  • Ingår i: Frontiers In Public Health. - : Frontiers Media SA. - 2296-2565. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Recently developed prismatic loupes may mitigate the high physical workload and risk of neck disorders associated with traditional surgical loupes among surgeons. However, research in this area, particularly among surgeons, is sparse. This study examines the impact of prismatic loupes on surgeons’ physical workload, musculoskeletal discomfort, and performance during simulated surgical tasks. Materials and methods: Nineteen out of twenty recruited surgeons performed three tasks in a fixed-order with their own loupes and both low-tilt (LT) and high-tilt (HT) prismatic loupes, in a randomized order. The primary outcomes were the median inclination angles and velocities of the head, trunk, and upper arms, along with the median muscle activity of the cervical erector spinae (CES), upper trapezius (UT), and lumbar erector spinae (LES) for each pair of loupes. The secondary outcomes included performance (completion time and errors), perceived body-part discomfort, and subjective evaluation of the three pairs of loupes. Results: Using prismatic loupes, either LT or HT, compared with the surgeons’ own loupes yielded lower head inclinations (all p < 0.001), lower neck muscle activity (all p < 0.05), and lower neck discomfort in indirect comparisons (p < 0.01) with no significant difference in surgical errors (p = 0.628). However, HT loupes resulted in a longer task completion time in two tasks (p < 0.001). Most surgeons preferred LT loupes (N = 12) for their comfort and visual functions. Discussion: The results indicate that prismatic loupes can reduce physical workload in the neck during simulated surgical task, with no significant difference in surgical errors. Future studies are needed to investigate the long-term effects of prismatic loupes among surgeons.
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  • Fotouhi, Omid, et al. (författare)
  • Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors
  • 2019
  • Ingår i: Oncogene. - : NATURE PUBLISHING GROUP. - 0950-9232 .- 1476-5594. ; 38:43, s. 6881-6897
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET.
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  • Gerdtsson, Axel, et al. (författare)
  • Surgical Complications in Postchemotherapy Retroperitoneal Lymph Node Dissection for Nonseminoma Germ Cell Tumour : A Population-based Study from the Swedish Norwegian Testicular Cancer Group
  • 2020
  • Ingår i: European Urology Oncology. - : Elsevier BV. - 2588-9311. ; 3:3, s. 382-389
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Reports on perioperative complications after postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for nonseminoma germ cell tumour (NSGCT) are from experienced single centres, with a lack of population-based studies. OBJECTIVE: To assess the complications of bilateral and unilateral PC-RPLND. DESIGN, SETTING, AND PARTICIPANTS: A prospective, population-based, observational multicentre study included all patients with NSGCT who underwent PC-RPLND in Norway and Sweden during 2007-2014. Of a total of 318 patients, 87 underwent bilateral PC-RPLND and 231 underwent unilateral PC-RPLND. The median follow-up was 6 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Bilateral and unilateral PC-RPLND were compared for the outcomes of intra- and postoperative complications (graded by Clavien-Dindo) and retrograde ejaculation (with or without nerve-sparing surgery). Complications were reported as absolute counts and percentages. The χ2 test was used for comparisons. RESULTS AND LIMITATIONS: The incidence of intraoperative complications was higher for bilateral PC-RPLND than for unilateral PC-RPLND (14% vs 4.3%, p = 0.003), with ureteral injury as the most frequent reported complication (2% of the patients). Postoperative complications were more common after bilateral than after unilateral PC-RPLND (45% vs 25%, p = 0.001) with Clavien ≥3b reported in 8.3% and 2.2%, respectively (p = 0.009). Lymphatic leakage was the most common complication occurring in 11% of the patients. Retrograde ejaculation occurred more frequently after bilateral than after unilateral surgery (59% vs 32%, p < 0.001). Limitations of the study include reporting of retrograde ejaculation, which was based on a chart review. CONCLUSIONS: Intra- and postoperative complications including retrograde ejaculation are more frequent after bilateral PC-RPLND than after unilateral PC-RPLND. PATIENT SUMMARY: Lymph node dissection in patients with testicular cancer puts them at risk of complications. In this study, we present the complications after lymph node dissection.
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  • Gerdtsson, Axel, et al. (författare)
  • Unilateral or Bilateral Retroperitoneal Lymph Node Dissection in Nonseminoma Patients with Postchemotherapy Residual Tumour? Results from RETROP, a Population-based Mapping Study by the Swedish Norwegian Testicular Cancer Group
  • 2022
  • Ingår i: European Urology Oncology. - : Elsevier BV. - 2588-9311. ; 5:2, s. 235-243
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The distribution of retroperitoneal lymph node metastases for patients with nonseminoma and a residual tumour of 10-49 mm in a population-based setting is unknown. This information is needed to justify selection of patients for a unilateral template resection. OBJECTIVE: To describe the location of retroperitoneal metastases and recurrences in patients with nonseminoma germ cell tumour (NSGCT) with a residual tumour of 10-49 mm. DESIGN, SETTING, AND PARTICIPANTS: RETROP is a population-based prospective observational mapping study of 213 patients in Sweden and Norway with a retroperitoneal residual tumour of 10-49 mm who underwent postchemotherapy retroperitoneal lymph node dissection for metastatic NSGCT during 2007-2014 with median follow-up of 100 mo. Patients were classified according to the testis primary tumour and the distribution of unilateral or bilateral lymph node metastases (with reference to the aorta) present on pre- and/or postchemotherapy computed tomography (CT) scans. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The distribution and rate of teratoma or cancer in unilateral or bilateral retroperitoneal fields and the location and rate of retroperitoneal recurrence were measured. RESULTS AND LIMITATIONS: In total, 65% of the patients had unilateral retroperitoneal lymph node metastases (RLNMs) on CT scans. Patients with unilateral RLNMs had a low risk of contralateral teratoma or cancer (1.6% for right- and 2.6% for left-sided NSGCT) or retroperitoneal recurrence (0% for right- and 4% for left-sided NSGCT). A weakness of the study is that the pathology specimen could not be fully designated to one specific area for some of the patients. CONCLUSIONS: Men with postchemotherapy residual disease of 10-49 mm and unilateral metastases on pre- and postchemotherapy CT scans have a low risk of contralateral disease and should be considered for a unilateral template resection. PATIENT SUMMARY: The surgeon can use computed tomography (CT) scans in deciding on the extent of lymph node dissection in patients with testicular cancer.
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  • Honeth, Gabriella, et al. (författare)
  • Chemokine-directed migration of tumor-inhibitory neural progenitor cells towards an intracranially growing glioma.
  • 2006
  • Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 312:8, s. 1265-1276
  • Tidskriftsartikel (refereegranskat)abstract
    • We have earlier shown that the rat neural progenitor cell line HiB5 is capable of suppressing intracranial growth of glioma cells in Fisher rats. Unlike some neural progenitor cells, HiB5 cells have not shown homing capacity towards glioma cells growing intracranially. In this study, we have genetically modified HiB5 progenitor cells to over-express the chemokine receptor CXCR3. We show that the introduced receptor is functionally responding to ligand stimulation with increased phosphorylation levels of ERK and SAPK/JNK and a transcriptional response of an AP-1 reporter system introduced into HIB5 cells. These transfected progenitor cells migrate in vitro in response to IP-10 and I-TAC. Further, we show an enhanced in vivo migration of the CXCR3 transfected HiB5 cells over the corpus callosum towards an IP-10 and I-TAC expressing glioma, as compared to wild type HiB5 cells. Our data indicate that it is possible to take advantage of chemokines natural capacity to initiate migratory responses, and to use this ability to enhance tumor-inhibitory neural progenitor cells to target an intracranially growing glioma.
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  • Höög, Anders, et al. (författare)
  • Somatostatin Receptor Expression in Renal Cell Carcinoma-A New Front in the Diagnostics and Treatment of Renal Cell Carcinoma
  • 2018
  • Ingår i: Clinical Genitourinary Cancer. - : CIG MEDIA GROUP, LP. - 1558-7673 .- 1938-0682. ; 16:3, s. E517-E520
  • Tidskriftsartikel (refereegranskat)abstract
    • Clinical Practice PointsRenal cell carcinoma (RCC) has a poor prognosis and is difficult to treat because of its ability to spread asymptomatically and its resistance to chemotherapy.In this patient series, we report that RCC metastases can be identified using gallium-68 (68Ga)-edotreotide (DOTATOC) positron emission tomography/computed tomography (PET/CT).Immunostaining of tumor tissue from primary RCC tumors and their matched adrenal, pancreatic, and thyroid metastases showed that RCC cells express membranous somatostatin receptor 2.These findings indicate that 68Ga-DOTATOC PET/CT can be used as a new imaging modality in management of metastatic RCC and might contribute to the development of new somatostatin analogue-based methods for the treatment of metastatic RCC.
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  • Jormfeldt, Mia (författare)
  • Tid, rum och självbestämmande : Möjligheter och hinder i vardagen för äldre personer med intellektuell funktionsnedsättning på gruppboende
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • People with intellectual disability are living longer, which creates new demands for the support and care of this target group. Participation and autonomy at all ages, regardless of functional capacity, are cited in legislation and among the key objectives of disability policy. As a group, older people with intellectual disability have previously been almost invisible in both policy documents and research. Information regarding this group is thus limited, and more systematic knowledge is needed about older people with intellectual disability, their daily lives, and especially their opportunities for autonomy.The purpose of this thesis is to learn more about the role of influence and autonomy in everyday life from the perspective of older people with intellectual disability living in group homes. This will be achieved by studying situations in which opportunities and obstacles arise for these residents to exercise their autonomy in daily life, and identifying and analysing how autonomy is expressed in the meeting between residents and staff.The study applies an ethnographic approach, using methods including field studies with observations and videotaped meetings between residents and staff. The sample consists of residents aged 65 and over and staff at three group homes for people with intellectual disability. One resident at each group home is followed in greater depth.The analysis uses the time-geographic concepts of project, activity and restrictions in order to clarify where and when different projects are carried out, as well as who has the power to determine what is to be carried out. Interaction analysis is used to analyse the videotaped meetings between residents and staff. The analysis is based on Goffman’s interaction order and interaction rituals, theories about turntaking, both verbal and non-verbal, and theories about power and counter-power. In accordance with Goffman’s framework concept, the starting point is the concrete framework that reflects spatiality, which in turn becomes a way to place the more abstract framework of the situation into a specific context.Two major projects were identified: Sleep and Rest and Meals. The analysis reveals projects that are governed by the resident’s own preferences (individual projects) and projects that are governed to a greater degree by the staff’s objectives and opportunities (institutional projects). Some guidance also derives from municipal decisions and guidelines (organizational projects). Many projects were carried out based on staff decisions and objectives, but in actual practice many projects failed to get off the ground. Some projects were at risk of failure until something happened or someone intervened and thereby rescued the project so that it could be implemented.The interactional analysis perspective shows how autonomy is constructed in the meeting. Autonomy is situation-bound, and shifts more on the basis of context than in relation to specific individuals. The study includes decision situations mainly between autonomy and its opposite, paternalism, which are viewed as extremes on a continuum. However, certain factors lead to stronger autonomy in certain situations. When a resident can define the situation, they also have greater power to determine the outcome. In situations characterized by paternalism, the staff have a preferential right of interpretation and the power to decide, both on the basis of their knowledge and because of the asymmetrical interdependence that characterizes the resident-professional relationship. Such situations are also governed by the rules and procedures of the group home to a greater degree than those situations in which the resident exercises autonomy.The thesis discusses strategies that could increase the residents’ opportunities for autonomy. Greater communication skills among staff can be viewed as a step on the path toward greater autonomy for the residents. Staff have the potential to eliminate obstacles, to strengthen inadequate skills or create new ones by providing choices and assistive devices, and to exercise an affirmative approach.
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  • Juhlin, Carl Christofer, et al. (författare)
  • Highly proliferative anal neuroendocrine carcinoma : molecular and clinical features of a rare, recurrent case in complete remission
  • 2020
  • Ingår i: BMC Gastroenterology. - : BMC. - 1471-230X. ; 20:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Poorly differentiated anal neuroendocrine carcinomas (ANECs) are rare lesions with poor prognosis, and the molecular etiology is only partially understood. Case presentation At our institution, we have treated and followed a patient with such a rare ANEC. He had primarily surgery followed by three rounds of repeated surgery for loco-regional recurrences. He also received three different combinations of chemotherapy and external beam radiation. At last follow-up 13 years since the primary diagnosis, the patient had been in complete remission for nine years. The patient's medical files were re-examined, including laboratory, radiology and clinical examinations. Histopathology was re-assessed, and expanded immunohistochemistry was performed from tissue specimens from the four surgical procedures. In addition, the molecular genetic status was evaluated through next-generation sequencing. The initial tumor was consistent with a 59 mm small cell neuroendocrine cancer with a Ki-67 index of 80%. Regional lymph node metastases were evident, and immunohistochemistry supported a neuroendocrine origin. A PCR screening detected human papilloma virus type 45 DNA (high-risk subtype), and focused next-generation sequencing found a missense mutation in thePhosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha(PIK3CA) gene. In tissues representing subsequent recurrences, the Chromogranin A expression was lost, and the Ki-67 index increased to 90%. Conclusions For the first time, we report the detection of HPV45 in a case of ANEC. To our belief,PIK3CAmutations have also not been previously demonstrated in this tumor entity. In highly malignant ANECs, cure can in rare cases be achieved. Although speculative, expression of HPV45 and/or thePIK3CAmutation may have contributed to the favorable outcome.
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  • Kjellman, Christian, et al. (författare)
  • Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma
  • 2000
  • Ingår i: International Journal of Cancer. - 0020-7136. ; 89:3, s. 251-258
  • Tidskriftsartikel (refereegranskat)abstract
    • Human gliomas express TGF-beta but, so far the expression of downstream mediators has been investigated in only a few cell lines. We have examined tissue specimens of 23 gliomas: 3 astrocytomas grade II (AST), 8 anaplastic astrocytomas grade III (AAST), and 12 glioblastoma multiforme grade IV (GBM). We analyzed the mRNA expression of TGF-beta1, TGF-beta2, TGF-beta3, the TGF-beta receptors type I (TbetaR-I) and type II (TbetaR-II), Smad2, Smad3, and Smad4. mRNA expression of IL-10 and CD95 (FAS/APO-1) were also studied. We detected increased mRNA levels of the 3 TGF-beta isoforms, correlating with the degree of malignancy. TGF-beta3 mRNA was increased, particularly in AST and AAST, while TGF-beta1 and TGF-beta2 mRNAs were strongly expressed in GBM. TGF-beta normally up-regulates the TGF-beta receptors, and TbetaR-I and TbetaR-II showed stronger expression in all gliomas when compared to normal tissues. However, the mRNA expression of Smad2, Smad3, and Smad4 was decreased in GBM. IL-10 mRNA expression was detected in glioma tissues but not in glioma cell lines. No marked increase in the expression of soluble CD95 splicing variants was found in the gliomas compared with normal tissue. However, total CD95 mRNA was elevated among GBM tissues.
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  • Kjellman, Magnus (författare)
  • Genetic characterization of adrenocortical tumors
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Adrenocortical cancer is a rare tumor form. However, adrenal tumors are today often found incidentally when using imaging techniques on the upper abdomen and should then be investigated. With the advance in molecular understanding of cancer new approaches to manage the disease may become available. We screened malignant and benign adrenocortical tumors (ACT) for gross genetic alterations using comparative genomic hybridization and microsatellite markers with the aim to find chromosomal regions that may harbour oncogenes, tumor suppressor genes, or mutator genes. Chromosomes 4 and 5 were found to possibly harbour oncogenes whereas chromosomes 2, 11, 17 and 18 may harbour tumor suppressor genes of importance for the development and progression of ACT. Furthermore, the study indicates that fundamental genetic changes take place in ACT larger than 4 cm. Because the tumor syndromes, Carney complex (CC) and Multiple endocrine neoplasia type I (MEN 1), are located on chromosome 2p16 and 11q13, respectively, these regions were further investigated. A one centi Morgan region, located distal to the CC locus, was defined by deletion mapping and may harbour TSGs of importance for the malignant transition of ACT. Furthermore, the 11q13 locus was frequently deleted in malignant ACT but no mutations were found in the MEN1 gene. It will be appropriate to investigate the transcriptional regulating region of the gene as well as epigenetic changes, such as the imprinting status. However, another gene(s) with TSG function may show to cause the frequent percentage of deletions at this locus. Another candidate gene, the IGF2 gene (11pl5) has been suggested to contribute to neoplastic cell proliferation and increase of its transcripts has been found in ACT. Studies of the IGF2 gene showed two novel splicing events which was also found in a Hep 3B cell line. The function of these splicing events is unknown. The suspected high prevalence of undiagnosed mild congenital adrenal hyperplasia (CAH), together with the high frequency of sporadic ACT in the population, has led to the speculation that mild undiagnosed CAH, or the heterozygous carrier state, is a predisposing factor for the development and/or progression of this tumor form. To investigate if mild CAH may be overrepresented in patients with apparently sporadic ACT we screened for constitutional mutations in the CYP21 gene. As no mutations were found we conclude that patients with ACT do not need to be screened for CAH. Gelatinase A is a metalloproteinase important in the process of tumor invasion and metastasis. Analyzes of mRNA expression of gelatinase A and its activator MT1-MMP showed increased levels in malignant as compared with benign ACT. These findings suggest that proteolytic enzymes are important for the malignant behaviour of ACT.
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26.
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27.
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28.
  • Laurell, Cecilia, et al. (författare)
  • Transcriptional profiling enables molecular classification of adrenocortical tumours
  • 2009
  • Ingår i: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 161:1, s. 141-152
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Tumours in the adrenocortex are common human tumours. Malignancy is however, rare, the yearly incidence being 0.5-2 per million inhabitants, but associated with a very aggressive behaviour. Adrenocortical tumours are often associated with altered hormone production with a variety of clinical symptoms. The aggressiveness of carcinomas together with the high frequency of adenomas calls for a deeper understanding of the underlying biological mechanisms and an improvement of the diagnostic possibilities. Methods: Microarray gene expression analysis was performed in tumours of adrenocortex with emphasis on malignancy as well as hormonal activity. The sample set consisted of 17 adenomas, 11 carcinomas and 4 histological normal adrenocortexes. RNA from these was hybridised according to a reference design on microarrays harbouring 29 760 human cDNA clones. Confirmation was performed with quantitative real time-PCR and western blot analysis. Results: Unsupervised clustering to reveal relationships between samples based on the entire gene expression profile resulted in two subclusters; carcinomas and non-cancer specimens. A large number of genes were accordingly found to be differentially expressed comparing carcinomas to adenomas. Among these were IGF2, FGFR1 and FGFR4 in growth factor signalling the most predominant and also the USP4, UBE2C and UFD1L in the ubiquitin-proteasome pathway. Moreover, two subgroups of carcinomas were identified with different survival outcome, suggesting that survival prediction can be made on the basis of gene expression profiles. Regarding adenomas with aldosterone overproduction, OSBP and VEGFB were among the most up-regulated genes compared with the other samples. Conclusions: Adrenocortical carcinomas are associated with a distinct molecular signature apparent in their gene expression profiles. Differentially expressed genes were identified associated with malignancy, survival as well as hormonal activity providing a resource of candidate genes for an exploration of possible drug targets and diagnostic and prognostic markers.
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29.
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30.
  • Lindskog, Magnus, et al. (författare)
  • Ilixadencel, a Cell-based Immune Primer, plus Sunitinib Versus Sunitinib Alone in Metastatic Renal Cell Carcinoma: A Randomized Phase 2 Study
  • 2022
  • Ingår i: European Urology Open Science. - : Elsevier BV. - 2666-1691 .- 2666-1683. ; 40, s. 38-45
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The prognosis of patients with synchronous metastatic renal cell carcinoma (mRCC) is poor. Whereas single-agent tyrosine kinase inhibition (TKI) is clearly insufficient, the effects can be enhanced by combinations with immune checkpoint inhibitors. Innovative treatment options combining TKI and other immune-stimulating agents could prove beneficial. Objective: To evaluate the clinical effects on metastatic disease when two doses of allogeneic monocyte-derived dendritic cells (ilixadencel) are administrated intratumorally followed by nephrectomy and treatment with sunitinib compared with nephrectomy and sunitinib monotherapy, in patients with synchronous mRCC. Design, setting, and participants: A randomized (2:1) phase 2 multicenter trial enrolled 88 patients with newly diagnosed mRCC to treatment with the combination ilixadencel/sunitinib (ILIXA/SUN; 58 patients) or sunitinib alone (SUN; 30 patients).Outcome measurements and statistical analysis: The primary endpoints were 18mo survival rate and overall survival (OS). A secondary endpoint was objective response rate (ORR) assessed up to 18 mo after enrollment. Statistic evaluations included Kaplan-Meier estimates, log-rank tests, Cox regression, and stratified Cochran-Mantel-Haenszel tests.Results and limitations: The median OS was 35.6 mo in the ILIXA/SUN arm versus 25.3 mo in the SUN arm (hazard ratio 0.73, 95% confidence interval 0.42-1.27; p = 0.25), while the 18-mo OS rates were 63% and 66% in the ILIXA/SUN and SUN arms, respectively. The confirmed ORR in the ILIXA/SUN arm were 42.2% (19/45), including three patients with complete response, versus 24.0% (six/25) in the SUN arm (p = 0.13) without complete responses. The study was not adequately powered to detect modest differences in survival. Conclusions: The study failed to meet its primary endpoints. However, ilixadencel in combination with sunitinib was associated with a numerically higher, nonsignificant, confirmed response rate, including complete responses, compared with sunitinib monotherapy.Patient summary: We studied the effects of intratumoral vaccination with ilixadencel followed by sunitinib versus sunitinib only in a randomized phase 2 study. The combination treatment showed numerically higher numbers of confirmed responses, suggesting an immunologic effect.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).
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31.
  • Rhen, Ida-Märta, 1975, et al. (författare)
  • A possible revival of population-representing digital human manikins in static work situations - exemplified through an evaluation of a prototype console for robotic surgery
  • 2021
  • Ingår i: Work. - : IOS Press. - 1051-9815 .- 1875-9270. ; 70:3, s. 833-851
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: In the 90s, digital human manikins (DHMs) were introduced in planning ofworkstations, by static or semi-static simulations. Modern DHMs can simulate dynamic work and offer a rapid way for a virtual pre-production ergonomic evaluation. Work-related musculoskeletal disorders may affect surgical performance and patient safety. A prototype of an open console, which is contrary to the conventional closed consoles and may be seen as a representative for a new generation, has been designed to reduce workload for robotic surgery surgeons. OBJECTIVE: The aim of this project was to test a new DHM tool with improved usability to evaluate the ergonomics of a console of a robotic surgical system in a pre-production stage. METHODS: The DHM tool IMMA was used together with a 3D model of the prototype console. Twelve manikins who represented females and males from two national populations were introduced. Manikin-console distances, after console adjustments per manikin, were compared with a US checklist and Swedish standard for VDU work. RESULTS: The DHM tool was useful for this case, but the distances of the checklist and the standard were needed to be obtained "manually". The automatic functions of the DHM worked smoothly but were not optimized for VDU work. The prototype fulfilled most, but not all, of the ergonomic criteria of the checklist and the standard. CONCLUSIONS: There is room for improvements of the adjustable ranges of the console prototype. DHMs may facilitate rapid pre-production evaluation of workstations for static work; if ergonomic assessment models for VDU work are built-in, there may be a revival of DHMs in static work situations.
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32.
  • Rosenblad, Andreas, Fil. dr, 1973-, et al. (författare)
  • Surgical waiting times and all-cause mortality in patients with non-metastatic renal cell carcinoma
  • 2022
  • Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 56:5-6, s. 383-390
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To examine the association between surgical waiting times (SWTs) and all-cause mortality (ACM) in non-metastatic patients with RCC, in relation to tumour stage. Patients and methods This nation-wide population-based cohort study included 9,918 M0 RCC patients registered in the National Swedish Kidney Cancer Register, between 2009 and 2021, followed-up for ACM until 9 December 2021, and having measured SWTs. The associations between primarily SWTs from date of radiological diagnosis to date of surgery (WRS) and secondarily SWTs from date of radiological diagnosis to date of treatment decision (WRT) and date of treatment decision to date of surgery (WTS), in relation to ACM, were analysed using Cox regression analysis, adjusted for clinical and demographic characteristics, stratified and unstratified according to T-stage. Results During a mean follow-up time of 5 years (49,873 person-years), 23% (n = 2291) of the patients died. The adjusted hazard ratio (AHR) for WRS (months) for all patients was 1.03 (95% confidence interval [CI] = 1.02-1.04; p < 0.001). When subdividing WRS on T-stage, the AHRs were 1.03 (95% CI = 1.01-1.04; p < 0.001) and 1.05 (95% CI = 1.02-1.08; p = 0.003) for stages T1 and T3, respectively, while non-significant for T2 (p = 0.079) and T4 (p = 0.807). Similar results were obtained for WRT and WTS. Conclusions Prolonged SWTs significantly increased the risk of early overall death among patients with RCC. The increased risk of early death from any cause show the importance of shortening SWTs in clinical work of patients with this malignant disease.
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33.
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34.
  • Tideman, Magnus, 1959-, et al. (författare)
  • Young adults with intellectual disability – self organization
  • 2013
  • Ingår i: NNDR2013 – 12th Research Conference Nordic Network of Disability Research. ; , s. 202-202
  • Konferensbidrag (refereegranskat)abstract
    • During later years it has become more common that young adults with intellectual disability organize themselves. Together they try to increase the power over their own lives and at the same time influence the community (local society) in the direction for increased participation. Those self-organized activities, self adovacy, can be understood as resistance against the society’s views and treatment of people with intellectual disability and against traditional ways to offer and organize support and service. The aim is to increase the knowledge about the new self-organized activities for young adults with intellectual disability in Sweden. The study will map/chart, describe and analyze 1) the meaning for the members and how the participation in the organization influence their identifications, self-determination, relations and daily life 2) the character of the organization and its activities, how they are organized and what they contain and 3) how the organization has influenced/changed the societies/environments attitudes and treatment. A strategically sample is based on the organizations relations to the established disability movement, i.e. both self-organized movements that exist as a section in the disability movement and those that are free-standing. With case studies, four organizations will be observed closely by using interview, group-interviews, observations and documentation analyzes. The self-organized movements indicate an important change in society and the project is expected to find results that are of importance for the target group and for shaping future support and treatment from society to persons with intellectual disabilities.
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35.
  • Velazquez-Fernandez, David, et al. (författare)
  • Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy.
  • 2005
  • Ingår i: Surgery. - : Elsevier BV. - 0039-6060 .- 1532-7361. ; 138:6, s. 1087-1094
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. Distinguishing between adrenocortical adenomas and carcinomas is often difficult. Our aim was to investigate the differences in transcriptional profiles between benign and malignant adrenocortical neoplasms using complementary DNA microarray techniques. Methods. We studied 7 patients with adrenocortical carcinomas and 13 with adenomas. Histopathology was reviewed in all patients, clinical follow-up was at least 1 year. Hybridizations were Performed in duplicate against RNA reference. Expression levels were analyzed in the R environment for statistical computing with the use of aroma, limma, statistics, and class packages. Results. Transcriptional profiles were homogeneous among adenomas, while carcinomas were much more heterogeneous. Hierarchical clustering and self-organizing maps could separate clearly carcinomas from adenomas. Among genes that were most significantly upregulated in carcinomas were 2 ubiquilin-related genes (USP4 and UFD1L) and several insulinlike growth factor-related genes (IGF2, IGF2R, IGFBP3 and IGFBP6). Among genes that were most significantly downregulated in carcinomas were a cylokine gene (CXCL10), several genes related to cell metabolism (RARRES2, ALDH1A1, CYBRD1 and GSTA4), and the cadherin 2 gene (CDH2). Conclusions. Through the use of cDNA arrays, adrenocortical adenomas and carcinomas appear to be clearly distinguishable on the basis of their specific molecular signature. The biologic importance of the up- and downregulated genes is yet to be determined.
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36.
  • Wells, Antonia C., et al. (författare)
  • Operating hurts : a study of EAES surgeons
  • 2019
  • Ingår i: Surgical Endoscopy. - : SPRINGER. - 0930-2794 .- 1432-2218. ; 33:3, s. 933-940
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundWork-related pain and discomfort experienced by surgeons is widely reported in the literature. A survey was, therefore, conducted to explore this issue among members of the European Association for Endoscopic Surgery (EAES).MethodsThe survey was emailed to 2980 EAES members in 2017 enquiring about their working practice, musculoskeletal (MSK) pain and burnout.ResultsA total of 569 (19%) surgeons responded, of whom 556 were practicing surgeons; 86% were consultants, 84% were male, and 94% were right-handed. Respondents operated on average 3.3days/week with 27% of their procedures lasting longer than 3h. The 386 endoscopists surveyed reported performing an average of 5.3 procedures/day with 83% performing endoscopy at least once per week. Over half of practicing surgeons (62%) reported their worst pain score was 3 or higher (10-point scale) in the past 7 working days, encompassing 71% of their open, 72% laparoscopic, 48% robot-assisted cases and 52% of their endoscopies. Of the 120 surgeons who had ever sought medical help for aches, pain or discomfort, 38% were currently in pain and 16% had considered leaving surgery due to their MSK pain, 26% had reported work-related pain to their employer, 26% had been on short-term disability during their career and 4% long-term disability due to MSK disorders. A significant proportion of the respondents (49%) felt their physical discomfort would influence the ability to perform or assist with surgical procedures in the future. These surgeons reported significantly lower satisfaction from their work (p=0.024), higher burnout (p=0.005) and significantly higher callousness toward people (p<0.001) than those not fearing loss of career longevity.ConclusionThe results show that MSK pain is prevalent amongst EAES members. Nearly half the respondents had career longevity fears from pain/discomfort which, in turn, correlated with more prevalent feelings of burnout. More emphasis should be placed on the aetiology, prevention and management of musculoskeletal pain in the surgical workforce.
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37.
  • Yu, Denny, et al. (författare)
  • Intraoperative workload in robotic surgery assessed by wearable motion tracking sensors and questionnaires
  • 2017
  • Ingår i: Surgical Endoscopy. - : Springer-Verlag New York. - 0930-2794 .- 1432-2218. ; 31:2, s. 877-886
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The introduction of robotic technology has revolutionized radical prostatectomy surgery. However, the potential benefits of robotic techniques may have trade-offs in increased mental demand for the surgeon and the physical demand for the assisting surgeon. This study employed an innovative motion tracking tool along with validated workload questionnaire to assess the ergonomics and workload for both assisting and console surgeons intraoperatively. Methods: Fifteen RARP cases were collected in this study. Cases were performed by 10 different participants, six primarily performed console tasks and four primarily performed assisting tasks. Participants had a median 12 (min—3, max—25) years of surgical experience. Both console and assisting surgeons performed robotic prostatectomy cases while wearing inertial measurement units (IMUs) that continuously track neck, shoulder, and torso motion without interfering with the sterile environment. Postoperatively, participants completed a workload questionnaire (SURG-TLX) and a body part discomfort questionnaire. Results: Twenty-six questionnaires were completed from 13 assisting and 13 console surgeons over the 15 cases. Postoperative pain was reported highest for the right shoulder and neck. Mental demands were 41 % higher for surgeons at the console than assisting (p < 0.05), while physical demands were not significantly different. Assisting surgeons worked in demanding neck postures for 58 % of the procedure compared to 24 % for the console surgeon (p < 0.01). Surgeons at the console were primarily static and showed 2–5 times fewer movements than assisting surgeons (p < 0.01). Conclusions: Postures were more ergonomic during console tasks than when assisting by the bedside; however, the console may constrain postures leading to static loads that have been associated with musculoskeletal symptoms for the neck, torso, and shoulders. The IMU sensors were effective at quantifying ergonomics in robotic prostatectomies, and these methods and findings have broad applications to other robotic procedures.
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38.
  • Audunson, Ragnar, et al. (författare)
  • 2004
  • Ingår i: Utvärdering av ämnena arkivvetenskap, biblioteks- och informationsvetenskap, bok- och bibliotekshistoria, informations- och medievetenskap, kulturvård och museologi vid svenska universitet och högskolor. - Stockholm : Högskoleverket. ; , s. 41-61
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)
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