1. |
- Liu, Yuanhua, 1971, et al.
(author)
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Considering the importance of user profiles in interface design
- 2009
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In: User Interfaces. ; , s. 23-
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Book chapter (other academic/artistic)abstract
- User profile is a popular term widely employed during product design processes by industrial companies. Such a profile is normally intended to represent real users of a product. The ultimate purpose of a user profile is actually to help designers to recognize or learn about the real user by presenting them with a description of a real user’s attributes, for instance; the user’s gender, age, educational level, attitude, technical needs and skill level. The aim of this chapter is to provide information on the current knowledge and research about user profile issues, as well as to emphasize the importance of considering these issues in interface design. In this chapter, we mainly focus on how users’ difference in expertise affects their performance or activity in various interaction contexts. Considering the complex interaction situations in practice, novice and expert users’ interactions with medical user interfaces of different technical complexity will be analyzed as examples: one focuses on novice and expert users’ difference when interacting with simple medical interfaces, and the other focuses on differences when interacting with complex medical interfaces. Four issues will be analyzed and discussed: (1) how novice and expert users differ in terms of performance during the interaction; (2) how novice and expert users differ in the perspective of cognitive mental models during the interaction; (3) how novice and expert users should be defined in practice; and (4) what are the main differences between novice and expert users’ implications for interface design. Besides describing the effect of users’ expertise difference during the interface design process, we will also pinpoint some potential problems for the research on interface design, as well as some future challenges that academic researchers and industrial engineers should face in practice.
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3. |
- Bin Kaderi, Mohamed Arifin, 1978-
(author)
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Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
- 2010
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Doctoral thesis (other academic/artistic)abstract
- The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL. In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL. In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results. In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.
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4. |
- Cutas, Daniela, 1978, et al.
(author)
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Legal imperialism in the regulation of stem cell research and therapy: the problem of extraterritorial jurisdiction
- 2010
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In: Capps BJ & Campbell AV (eds.). CONTESTED CELLS: Global Perspectives on the Stem Cell Debate. - London : Imperial College Press. - 9781848164376 ; , s. 95-119
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Book chapter (other academic/artistic)abstract
- Countries worldwide have very different national regulations on human embryonic stem (ES) cell research, informed by a range of ethical values. Some countries find reason to extend the applicability of their regulations on such research to its citizens when they visit other countries. Extraterritorial jurisdiction has recently been identified as a potential challenge towards global regulation of ES cell research. This chapter explores the implications and impact of extraterritorial jurisdiction and global regulation of ES cell research on researchers, clinicians and national health systems, and how this may affect patients. The authors argue that it would make ethical sense for ES cell restrictive countries to extend its regulations on ES cell research beyond its borders, because, if these countries really consider embryo destruction to be objectionable on the basis on the status of the embryo, then they ought to count it morally on par with murder (and thus have a moral imperative to protect embryos from the actions of its own citizens). However, doing so could lead to a legal situation that would result in substantial harm to central values in areas besides research, such as health care, the job market, basic freedom of movement, and strategic international finance and politics. Thus, it seems that restrictive extraterritorial jurisdiction in respect to ES cell research would be deeply problematic, given that the ethical permissibility of ES cell research is characterised by deep and wide disagreement.
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5. |
- Munthe, Christian, 1962
(author)
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Etiska aspekter på regenerativ medicin : Ethical aspects on regenerative medicine
- 2003
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In: SNIB-konferensen 2003, Chalmers tekniska högskola, Göteborg, 16-18 maj 2003.
-
Conference paper (other academic/artistic)abstract
- Inom den regenerativa medicinen strävar man efter att ersätta skadat eller sjukligt biologiskt mänskligt material (celler, organ, kroppsdelar) med nya biologiska komponenter. Området aktualiserar en rad etiska frågeställningar vad gäller (1) produktionen av ersättningsmaterialet (t.ex. embryonala stamceller eller införskaffande av transplantationsvävnad från donatorer), (2) risker i samband med försök på människa (genmodifierat material, material från djur), samt (3) gränserna för hur långt man bör gå i denna slags försök att förlänga människans livsspann. Föredraget ger en kort översikt över dessa frågeställningar, ståndpunkter och argument i debatten kring dem.
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6. |
- Lindmark, Ulrika, 1965-, et al.
(author)
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Health-promoting factors in higher education for a sustainable working life : protocol for a multicenter longitudinal study
- 2020
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In: BMC Public Health. - London : BioMed Central. - 1471-2458. ; 20:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: The World Health Organization has highlighted the importance of health promotion for health service providers in order to ensure sustainable working life for individuals involved in providing health services. Such sustainability begins when students are preparing to manage their own future health and welfare in working life. It has been suggested that universities, employees and trainee health professionals should adopt or follow a salutogenic approach that not only complements the providing of information on known health risks but also favors health promotion strategies. This paper describes the study design and data collection methods in a planned study aiming to explore health-promoting factors for a sustainable working life among students in higher education within healthcare and social work. METHODS: This protocol describes a multicenter longitudinal study involving Swedish students on higher education programs in the healthcare and social work sectors. In 2018, the study invited students on seven education programs at six universities to participate. These programs were for qualification as: biomedical laboratory scientists (n = 121); dental hygienists (n = 87); nurses (n = 1411); occupational therapists (n = 111); physiotherapists (n = 48); radiographers (n = 60); and, social workers (n = 443). In total, 2283 students were invited to participate. Participants completed a baseline, a self-reported questionnaire including six validated instruments measuring health-promoting factors and processes. There are to be five follow-up questionnaires. Three while the students are studying, one a year after graduating, and one three years after graduating. Each questionnaire captures different health-promoting dimensions, namely: health-promoting resources (i.e. sense of coherence); occupational balance; emotional intelligence; health and welfare; social interaction; and work and workplace experiences/perceptions. DISCUSSION: This study focuses on the vastly important aspect of promoting a sustainable working life for healthcare and social work employees. In contrast to previous studies in this area, the present study uses different, validated instruments in health promotion, taking a salutogenic approach. It is hoped that, by stimulating the implementation of new strategies, the study's findings will lead to education programs that prepare students better for a sustainable working life in healthcare and social work.
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7. |
- Teede, Helena J, et al.
(author)
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Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome.
- 2023
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In: Fertility and sterility. - 1556-5653. ; 120:4, s. 767-793
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Journal article (peer-reviewed)abstract
- What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference?International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS.The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist.The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout.This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC).The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management.Overall, recommendations are strengthened and evidence is improved, but remain generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided.The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation programme supports the Guideline with an integrated evaluation program.This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and the Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the sponsoring organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.
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8. |
- Björkman, Kristoffer, et al.
(author)
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Clinical course of patients with single large-scale mtDNA deletions and childhood onset anemia
- 2022
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In: 14th European Paediatric Neurology Society Congress, Glasgow, UK (ISBN 978-3-00-072065-9).
-
Conference paper (other academic/artistic)abstract
- Objective: To add to our knowledge of the clinical spectrum of patients with single large-scale mitochondrial DNA (mtDNA) deletion and childhood onset anemia. Methods: Retrospective collection of clinical data from medical records for patients, both living and deceased, with a single large-scale mtDNA deletion from seven mitochondrial disease centers in five countries. Statistical analysis with descriptive methods and Kaplan-Meier survival analysis. Results: Seventeen patients matching the genetic criterium and with anemia onset before six years of age. Exocrine pancreatic insufficiency was only seen in five patients in this group. Multiple organs were involved in all patients, with the most common non-hematologic ones being skeletal muscle, central nervous system, endocrine, eyes, gastrointestinal system, kidneys, hearing, liver and heart. Psychomotor retardation was seen in ten patients, hearing impairment in nine patients, failure to thrive in eight patients. Eight later developed Kearns-Sayre syndrome. Eleven patients were deceased, with a median age at death of 7.5 years. Conclusions: The classically described phenotype of patients with large-scale mtDNA deletions and early onset anemia is Pearson marrow-pancreas syndrome, characterized by sideroblastic anemia and exocrine pancreas dysfunction. Only a minority of our patients fulfill the original criteria of Pearson syndrome though. Involvement of other organs than the pancreas is more common. The clinical course vary, but multi-system impact is the rule and life-expectancy is low. Early onset anemia in patients with large-scale mtDNA deletions is most frequently not associated with exocrine pancreas dysfunction. Better knowledge of the phenotype is helpful for diagnosis and more accurate prognosis.
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9. |
- Böhmer, Jens, 1981, et al.
(author)
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Absolute Quantification of Donor-Derived Cell-Free DNA in Pediatric and Adult Patients After Heart Transplantation: A Prospective Study.
- 2023
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In: Transplant international : official journal of the European Society for Organ Transplantation. - 0934-0874 .- 1432-2277. ; 36
-
Journal article (peer-reviewed)abstract
- In this prospective study we investigated a cohort after heart transplantation with a novel PCR-based approach with focus on treated rejection. Blood samples were collected coincidentally to biopsies, and both absolute levels of dd-cfDNA and donor fraction were reported using digital PCR. 52 patients (11 children and 41 adults) were enrolled (NCT03477383, clinicaltrials.gov), and 557 plasma samples were analyzed. 13 treated rejection episodes >14days after transplantation were observed in 7 patients. Donor fraction showed a median of 0.08% in the cohort and was significantly elevated during rejection (median 0.19%, p < 0.0001), using a cut-off of 0.1%, the sensitivity/specificity were 92%/56% (AUC ROC-curve: 0.78). Absolute levels of dd-cfDNA showed a median of 8.8 copies/mL and were significantly elevated during rejection (median 23, p = 0.0001). Using a cut-off of 7.5 copies/mL, the sensitivity/specificity were 92%/43% for donor fraction (AUC ROC-curve: 0.75). The results support the feasibility of this approach in analyzing dd-cfDNA after heart transplantation. The obtained values are well aligned with results from other trials. The possibility to quantify absolute levels adds important value to the differentiation between ongoing graft damage and quiescent situations.
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10. |
- Berglund, Fanny, et al.
(author)
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Evidence for wastewaters as environments where mobile antibiotic resistance genes emerge
- 2023
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In: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 6
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Journal article (peer-reviewed)abstract
- The emergence and spread of mobile antibiotic resistance genes (ARGs) in pathogens have become a serious threat to global health. Still little is known about where ARGs gain mobility in the first place. Here, we aimed to collect evidence indicating where suchinitial mobilizationevents of clinically relevant ARGs may have occurred. We found that the majority of previously identified origin species did not carry the mobilizing elements that likely enabled intracellular mobility of the ARGs, suggesting a necessary interplay between different bacteria. Analyses of a broad range of metagenomes revealed that wastewaters and wastewater-impacted environments had by far the highest abundance of both origin species and corresponding mobilizing elements. Most origin species were only occasionally detected in other environments. Co-occurrence of origin species and corresponding mobilizing elements were rare in human microbiota. Our results identify wastewaters and wastewater-impacted environments as plausible arenas for the initial mobilization of resistance genes.
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11. |
- Lind, Anne-Li, et al.
(author)
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Affinity Proteomics Applied to Patient CSF Identifies Protein Profiles Associated with Neuropathic Pain and Fibromyalgia
-
Other publication (other academic/artistic)abstract
- Objective: Today, there are no biological tests on which to base pain diagnoses, treatment choices or to understand the biological processes underlying and accompanying chronic pain for the individual pain patient. Relevant biological markers would greatly aid in diagnosis and treatment of patients with chronic pain. Our study aimed to find proteins in CSF associated with fibromyalgia and neuropathic pain, two common and poorly understood chronic pain conditions.Methods: We have performed CSF protein profiling of 55 proteins using a 100-plex antibody suspension bead array. We collected, analyzed and compared CSF samples from 25 patients with neuropathic pain (two independent sets, n=14 patients for discovery and n=11 for verification), 40 patients with fibromyalgia and 135 controls without neurological disease from two different populations.Results: We found significant differences in CSF protein levels between patients and controls (p<0.05). Among these proteins, Apolipoprotein C1 (APOC1) was found to be increased in CSF of neuropathic pain patients compared to controls and there was a non-significant trend for increased levels also in fibromyalgia patient CSF. Ectonucleotide pyrophosphatase (ENPP2, Autotaxin) was increased in the CSF of fibromyalgia patients compared to all other groups including neuropathic pain patients. Multivariate analysis revealed partially overlapping and partially distinct CSF profiles in neuropathic pain patients compared with fibromyalgia and controls for several other proteins including angiotensinogen (AGT), prostaglandin-H2 D-isomerase (PTGDS), neurexin-1 (NRXN1), superoxide dismutase 1 (SOD1) and superoxide dismutase 3 (SOD3).Conclusions: Our results, suggest that the CSF protein profiles of neuropathic pain and fibromyalgia patients may be different from each other and from those of controls. CSF levels of APOC1, ENPP2, AGT, PTGDS, NRXN1, SOD1 and SOD3 should be further investigated for their potential to serve as biomarkers of different kinds of pain pathophysiology.
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12. |
- Lind, Anne-Li
(author)
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Biomarkers for Better Understanding of the Pathophysiology and Treatment of Chronic Pain : Investigations of Human Biofluids
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Chronic pain affects 20 % of the global population, causes suffering, is difficult to treat, and constitutes a large economic burden for society. So far, the characterization of molecular mechanisms of chronic pain-like behaviors in animal models has not translated into effective treatments.In this thesis, consisting of five studies, pain patient biofluids were analyzed with modern proteomic methods to identify biomarker candidates that can be used to improve our understanding of the pathophysiology chronic pain and lead to more effective treatments.Paper I is a proof of concept study, where a multiplex solid phase-proximity ligation assay (SP-PLA) was applied to cerebrospinal fluid (CSF) for the first time. CSF reference protein levels and four biomarker candidates for ALS were presented. The investigated proteins were not altered by spinal cord stimulation (SCS) treatment for neuropathic pain. In Paper II, patient CSF was explored by dimethyl and label-free mass spectrometric (MS) proteomic methods. Twelve proteins, known for their roles in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity, were identified to be associated with SCS treatment of neuropathic pain. In Paper III, proximity extension assay (PEA) was used to analyze levels of 92 proteins in serum from patients one year after painful disc herniation. Patients with residual pain had significantly higher serum levels of 41 inflammatory proteins. In Paper IV, levels of 55 proteins were analyzed by a 100-plex antibody suspension bead array (ASBA) in CSF samples from two neuropathic pain patient cohorts, one cohort of fibromyalgia patients and two control cohorts. CSF protein profiles consisting of levels of apolipoprotein C1, ectonucleotide pyrophosphatase/phosphodiesterase family member 2, angiotensinogen, prostaglandin-H2 D-isomerase, neurexin-1, superoxide dismutases 1 and 3 were found to be associated with neuropathic pain and fibromyalgia. In Paper V, higher CSF levels of five chemokines and LAPTGF-beta-1were detected in two patient cohorts with neuropathic pain compared with healthy controls.In conclusion, we demonstrate that combining MS proteomic and multiplex antibody-based methods for analysis of patient biofluid samples is a viable approach for discovery of biomarker candidates for the pathophysiology and treatment of chronic pain. Several biomarker candidates possibly reflecting systemic inflammation, lipid metabolism, and neuroinflammation in different pain conditions were identified for further investigation.
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13. |
- Handlin, Linda, 1981-, et al.
(author)
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Promoting health of Swedish workers by complementary methods : example of a study design of a longitudinal randomized controlled intervention study
- 2017
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In: Medical Research Archives. - USA : KEI Journals. - 2375-1916 .- 2375-1924. ; 5:8, s. 1-13
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Journal article (peer-reviewed)abstract
- Background: When designing, implementing, and evaluating a work site health promotion program, it is necessary to ensure that the program is evidence based. The present article aims to present in-depth information on the design of a longitudinal randomized controlled complementary intervention pilot study that follows the Consort recommendations to evaluate possible effects of a health promotive intervention in healthy workers.Methods: Employees from four different workplaces were randomly assigned to one of the following groups: i) Massage and mental training (sitting in the armchair and receiving mechanical massage while listening to mental training programs, n=19), ii) Massage (sitting in the armchair and receiving mechanical massage only, n=19), iii) Mental training (sitting in the armchair and listening to mental training programs only, n=19), iv) Pause (sitting in the armchair but not receiving mechanical massage or listening to mental training programs, n=19), v) Control (not sitting in the armchair at all, n=17). The study lasted for eight weeks. Immediately before the randomization, after four weeks and after eight weeks the participants responded to statements from the Swedish Scale of Personality and had their heart rate, blood pressure and fingertip temperature measured.Results: Receiving mechanical massage and listening to mental training programs, either separately or in combination, during working hours had some positive effects on the employees’ own evaluation of their health, as well as their heart rate, blood pressure and fingertip temperature. However, the intervention need to be evaluated further.Conclusion: The approach described makes it possible to design, implement and evaluate a work site health promotion program, also on pilot-study level and these results should be seen as a first step towards larger randomized studies. This types of studies need to focus on healthy participants and special care should be taken to guarantee adequately powered study groups and their homogeneity.
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15. |
- Schöll, Michael, 1980, et al.
(author)
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Biomarkers for tau pathology.
- 2019
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In: Molecular and cellular neurosciences. - : Elsevier BV. - 1095-9327 .- 1044-7431. ; 97, s. 18-33
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Research review (peer-reviewed)abstract
- The aggregation of fibrils of hyperphosphorylated and C-terminally truncated microtubule-associated tau protein characterizes 80% of all dementia disorders, the most common neurodegenerative disorders. These so-called tauopathies are hitherto not curable and their diagnosis, especially at early disease stages, has traditionally proven difficult. A keystone in the diagnosis of tauopathies was the development of methods to assess levels of tau protein in vivo in cerebrospinal fluid, which has significantly improved our knowledge about these conditions. Tau proteins have also been measured in blood, but the importance of tau-related changes in blood is still unclear. The recent addition of positron emission tomography ligands to visualize, map and quantify tau pathology has further contributed with information about the temporal and spatial characteristics of tau accumulation in the living brain. Together, the measurement of tau with fluid biomarkers and positron emission tomography constitutes the basis for a highly active field of research. This review describes the current state of biomarkers for tau biomarkers derived from neuroimaging and from the analysis of bodily fluids and their roles in the detection, diagnosis and prognosis of tau-associated neurodegenerative disorders, as well as their associations with neuropathological findings, and aims to provide a perspective on how these biomarkers might be employed prospectively in research and clinical settings.
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16. |
- Malmström, Annika, 1957-
(author)
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Studies for Better Treatment of Patients with Glioma
- 2019
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Doctoral thesis (other academic/artistic)abstract
- In Sweden annually over 500 people will be diagnosed with the malignant brain tumor glioma. They are graded from I-IV. The majority are glioblastoma (grade IV) (GBM), these being the most aggressive type. Median survival for those treated with standard of care is expected to be around 15 months. This tumor will mainly affect those 60 years or older.The studies in this thesis focus on treatment of patients with malignant gliomas grade III and IV. The aim of the studies is to improve the care of glioma patients. Papers I and II explored different therapeutic options in randomized trials, to facilitate individualized treatment recommendations. Findings from studies I and II, together with additional trials, demonstrated the importance of analyzing the tumor marker O6-methylguanine DNA methyltransferase (MGMT) methylation status for survival of GBM patients treated with Temozolomide (TMZ). The third paper investigated how the analysis of this marker is implemented internationally.The first study (paper I, Nordic trial) investigated treatment options for patients 60 years or older with GBM. The trial compared standard radiotherapy (SRT) over 6 weeks versus hypofractionated radiotherapy (HRT) over 2 weeks versus single agent TMZ administered in up to six 4 weekly cycles. In all, 342 patients were included in the trial. This study demonstrated that those randomized to TMZ had superior survival as compared to SRT. In addition, quality of life (QoL) data also suggested a better QoL for TMZ treatment than for radiotherapy. The benefit of TMZ treatment seemed to be limited to those with the tumor molecular marker MGMT methylated (inactivated).The second trial (paper II, Neoadjuvant trial) studied whether integrating TMZ treatment with SRT for patients younger than 60 years with GBM (grade IV) and astrocytoma grade III would confer a survival benefit, if administered postoperatively, before the start of SRT (neoadjuvant). TMZ was provided for 2-3 four weekly cycles followed by SRT to patients randomized to neoadjuvant treatment and was compared to postoperative SRT alone. Although this trial could not illustrate any advantage of delaying the start of SRT while administering TMZ for the study cohort in general, for those included as astrocytoma grade III the median survival was found to be superior by 5 years when randomized to neoadjuvant TMZ. This trial also confirmed the importance of MGMT promoter methylation for the efficacy of TMZ.The third study (paper III) investigated international practices for analyzing tumor MGMT promoter methylation status. MGMT analysis can be conducted by various laboratory methods, which in some cases can provide opposing results regarding the MGMT methylation status of the patient´s tumor. This can lead to incorrect treatment recommendations. To establish which methods and cut-offs that are regularly used to determine tumor MGMT status in the clinic, an international survey was provided to those working in the field. We also inquired about opinions regarding an international consensus on how MGMT should be tested. The 152 respondents reported several methodologies and different cut-off levels also for the same method. A majority of respondents warrant international guidelines.In conclusion, the results of the 2 randomized trials contribute to individualized treatment recommendations for patients affected by GBM or astrocytoma grade III. The results of the survey regarding analyses of MGMT clarify the current problematic situation. The request of the respondents regarding international guidelines might contribute to their future development, so that personalized treatment recommendations can be improved.
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17. |
- Wilms, Torben, 1973-
(author)
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Squamous cell carcinoma of the head and neck, focusing on Epstein-Barr-virus, programmed cell death ligand 1 and serum lipoproteins
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Background: Squamous cell carcinoma of the head and neck (SCCHN)comprises a large group of tumours including the oral cavity and nasopharyngealarea, and typically affects older males in association with alcohol/tobacco usage.Within the oral cavity, the mobile tongue is the most common site for tumourdevelopment. The incidence of squamous cell carcinoma of the oral tongue(SCCOT) is increasing in younger people, which has been suggested to associatewith other than the traditional risk factors for this disease. Two common humanoncogenic viruses, human papillomavirus (HPV) and Epstein-Barr virus (EBV)are connected to certain types of SCCHN, in oropharynx and nasopharynxrespectively. The receptor programmed cell death 1 (PD)-1 and its ligandprogrammed cell death ligand 1 (PD-L1) are particularly relevant in immunecheckpoint control, and elevated levels have been seen in various cancer types. Alink between hyperlipidemia and cancer risk has previously been suggested. Theaim of this thesis was to investigate risk factors and prognostic features forSCCHN, by focusing on EBV, PD-L1 and serum lipoproteins.Materials and methods: Ninety-eight cases of SCCOT and 15 cases of tonsillarsquamous cell carcinoma were examined for the presence of EBV-encodedribonucleic acids (EBERs), EBV deoxyribonucleic acid (DNA) and the proteinEBV-encoded nuclear antigen-1 (EBNA-1), using in situ hybridisation,polymerase chain reaction (PCR) and immunohistochemistry respectively. Onehundred and one cases of SCCOT were examined for expression of PD-L1 intumour and surrounding immune cells using Ventana SP263immunohistochemistry assay and a QuickScore (QS) method. An estimation oftumour-infiltrating immune cells was also performed in 25 of the patients.Circulating levels of PD-L1 were measured using an electrochemiluminescenceassay platform in serum from 30 patients. Finally, serum samples from 106patients and 28 healthy controls were investigated for levels of total cholesterol,low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides andlipoprotein(a).Results: In the first study, using an in situ hybridisation kit no EBER transcriptswere detected. No EBV DNA was identified with PCR analysis, andimmunohistochemistry for EBNA-1 was also negative. In the second study, highertumour cell PD-L1 levels were found in females than males (p = 0.019). Forpatients with low PD-L1 in tumour cells, better survival was shown in males thanfemales (overall survival p = 0.021, disease-free survival p = 0.020). Tumourinfiltrating natural killer (NK) T cells, immature dendritic cells (DCs) and M1macrophages correlated positively with tumour cell PD-L1 (p < 0.05). In the laststudy, the only lipoprotein showing significant difference in concentration iiibetween healthy controls and patients was HDL (p = 0.012). Kaplan-Meiersurvival curves showed that patients with high levels of total cholesterol or LDLhad better survival than patients with normal levels (p = 0.028 and p = 0.007respectively). Adjusting for the effects of age at diagnosis, TNM stage and weightchange, multivariate Cox regression models showed LDL to be an independentprognostic factor for both overall (p = 0.010) and disease-free survival (p =0.018).Conclusion: We excluded EBV as a potential player in SCCOT in both old andyoung patients and highlight the importance of appropriate controls for EBVencoded RNA in-situ hybridization (EBER-ISH) when investigating EBV inhuman diseases. Regarding PD-L1, our data supported the significance of genderon tumour cell PD-L1 expression and demonstrated combined effects of genderand PD-L1 levels on clinical outcome in patients with SCCOT. Data also indicatedthe involvement of specific immune cell types in PD-L1-regulated immuneevasion. Looking at serum lipoproteins, we found high LDL levels to be beneficialfor survival outcome in patients with SCCHN. Furthermore, the use of cholesterollowering medicine for prevention or management of SCCHN needs to be carefullyevaluated.
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18. |
- Bäckryd, Emmanuel, et al.
(author)
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High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain : a cross-sectional study of 2 cohorts of patients compared with healthy controls
- 2017
-
In: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 158:12, s. 2487-2495
-
Journal article (peer-reviewed)abstract
- Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called “gliotransmitters,” a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n = 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.
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19. |
- Nordberg, Marika, et al.
(author)
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Aetiology of tick-borne infections in an adult swedish population-are co-infections with multiple agents common
- 2014
-
In: Open Journal of Clinical Diagnostics. - Scientific Research : Scientific Research Publishing, Inc.. - 2162-5816 .- 2162-5824. ; 4:1, s. 31-40
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Journal article (peer-reviewed)abstract
- In Scandinavia, tick-borne infections affecting humans include Lyme borreliosis (LB), tick-borne encephalitis (TBE) and human granulocytic anaplasmosis (HGA). Each of these infections can present with unspecific symptoms. In this prospective clinical study, we recruited patients based on two independent inclusion criteria; 1) patients with unspecific symptoms, i.e. fever (≥38.0˚C) or a history of feverishness and/or any combination of headache, myalgia or arthralgia and 2) patients with erythema migrans (EM), following an observed tick bite or tick exposure within one month prior to onset of symptoms. A total of 206 patients fulfilled the study. Among these, we could identify 186 cases of LB (174 with EM), 18 confirmed and two probable cases of HGA and two cases of TBE. Thirteen of the HGA cases presented without fever. Furthermore, 22 of the EM patients had a sub-clinical co-infection with Anaplasma phagocytophilum, based on serology. Both TBE cases had co-infections, one with Borrelia burgdorferi and one with Anaplasma phagocytophilum. We conclude that it is important to consider several causative agents and possible co-infections in the clinical management of infectious diseases where ticks may be suspected as vectors.
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20. |
- Huvila, J., et al.
(author)
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Combined ASRGL1 and p53 immunohistochemistry as an independent predictor of survival in endometrioid endometrial carcinoma
- 2018
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In: Gynecologic Oncology. - : Academic Press Inc.. - 0090-8258 .- 1095-6859. ; 149:1, s. 173-180
-
Journal article (peer-reviewed)abstract
- Objective: In clinical practise, prognostication of endometrial cancer is based on clinicopathological risk factors. The use of immunohistochemistry-based markers as prognostic tools is generally not recommended and a systematic analysis of their utility as a panel is lacking. We evaluated whether an immunohistochemical marker panel could reliably assess endometrioid endometrial cancer (EEC) outcome independent of clinicopathological information. Methods: A cohort of 306 EEC specimens was profiled using tissue microarray (TMA). Cost- and time-efficient immunohistochemical analysis of well-established tissue biomarkers (ER, PR, HER2, Ki-67, MLH1 and p53) and two new biomarkers (L1CAM and ASRGL1) was carried out. Statistical modelling with embedded variable selection was applied on the staining results to identify minimal prognostic panels with maximal prognostic accuracy without compromising generalizability. Results: A panel including p53 and ASRGL1 immunohistochemistry was identified as the most accurate predictor of relapse-free and disease-specific survival. Within this panel, patients were allocated into high- (5.9%), intermediate- (29.5%) and low- (64.6%) risk groups where high-risk patients had a 30-fold risk (P < 0.001) of dying of EEC compared to the low-risk group. Conclusions: P53 and ASRGL1 immunoprofiling stratifies EEC patients into three risk groups with significantly different outcomes. This simple and easily applicable panel could provide a useful tool in EEC risk stratification and guiding the allocation of treatment modalities.
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21. |
- Parveen, Nagma, 1988, et al.
(author)
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Competition for Membrane Receptors: Norovirus Detachment via Lectin Attachment
- 2019
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 141:41, s. 16303-16311
-
Journal article (peer-reviewed)abstract
- Virus internalization into the host cells occurs via multivalent interactions, in which a single virus binds to multiple receptors in parallel. Because of analytical and experimental limitations this complex type of interaction is still poorly understood and quantified. Herein, the multivalent interaction of norovirus-like particles (noroVLPs) with H or B type 1 glycosphingolipids (GSLs), embedded in a supported phospholipid bilayer, is investigated by following the competition between noroVLPs and a lectin (from Ralstonia solanacearum) upon binding to these GSLs. Changes in noroVLP and lectin coverage, caused by competition, were monitored for both GSLs and at different GSL concentrations using quartz crystal microbalance with dissipation monitoring. The study yields information about the minimum GSL concentration needed for (i) noroVLPs to achieve firm attachment to the bilayer prior to competition and to (ii) remain firmly attached to the bilayer during competition. We show that these two concentrations are almost identical for the H type 1-noroVLP interaction but differ for B type 1, indicating an accumulation of B type 1 GSLs in the noroVLP-bilayer interaction area. Furthermore, the GSL concentration required for firm attachment is significantly larger for H type 1 than for B type 1, indicating a higher affinity of noroVLP toward B type 1. This finding is supported by extracting the energy of single noroVLP-H type 1 and noroVLP-B type 1 bonds from the competition kinetics, which were estimated to be 5 and 6 kcal/mol, respectively. This demonstrates the potential of utilizing competitive binding kinetics to analyze multivalent interactions, which has remained difficult to quantify using conventional approaches.
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22. |
- Senkowski, Wojciech
(author)
-
High-throughput screening using multicellular tumor spheroids to reveal and exploit tumor-specific vulnerabilities
- 2017
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Doctoral thesis (other academic/artistic)abstract
- High-throughput drug screening (HTS) in live cells is often a vital part of the preclinical anticancer drug discovery process. So far, two-dimensional (2D) monolayer cell cultures have been the most prevalent model in HTS endeavors. However, 2D cell cultures often fail to recapitulate the complex microenvironments of in vivo tumors. Monolayer cultures are highly proliferative and generally do not contain quiescent cells, thought to be one of the main reasons for the anticancer therapy failure in clinic. Thus, there is a need for in vitro cellular models that would increase predictive value of preclinical research results. The utilization of more complex three-dimensional (3D) cell cultures, such as multicellular tumor spheroids (MCTS), which contain both proliferating and quiescent cells, has therefore been proposed. However, difficult handling and high costs still pose significant hurdles for application of MCTS for HTS.In this work, we aimed to develop novel assays to apply MCTS for HTS and drug evaluation. We also set out to identify cellular processes that could be targeted to selectively eradicate quiescent cancer cells. In Paper I, we developed a novel MCTS-based HTS assay and found that nutrient-deprived and hypoxic cancer cells are selectively vulnerable to treatment with inhibitors of mitochondrial oxidative phosphorylation (OXPHOS). We also identified nitazoxanide, an FDA-approved anthelmintic agent, to act as an OXPHOS inhibitor and to potentiate the effects of standard chemotherapy in vivo. Subsequently, in Paper II we applied the high-throughput gene-expression profiling method for MCTS-based drug screening. This led to discovery that quiescent cells up-regulate the mevalonate pathway upon OXPHOS inhibition and that the combination of OXPHOS inhibitors and mevalonate pathway inhibitors (statins) results in synergistic toxicity in this cell population. In Paper III, we developed a novel spheroid-based drug combination-screening platform and identified a set of molecules that synergize with nitazoxanide to eradicate quiescent cancer cells. Finally, in Paper IV, we applied our MCTS-based methods to evaluate the effects of phosphodiesterase (PDE) inhibitors in PDE3A-expressing cell lines.In summary, this work illustrates how MCTS-based HTS yields potential to reveal and exploit previously unrecognized tumor-specific vulnerabilities. It also underscores the importance of cell culture conditions in preclinical drug discovery endeavors.
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23. |
- Javeed, Ashir, 1989-, et al.
(author)
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Predictive Power of XGBoost_BiLSTM Model : A Machine-Learning Approach for Accurate Sleep Apnea Detection Using Electronic Health Data
- 2023
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In: International Journal of Computational Intelligence Systems. - : Springer Nature. - 1875-6891 .- 1875-6883. ; 16:1
-
Journal article (peer-reviewed)abstract
- Sleep apnea is a common disorder that can cause pauses in breathing and can last from a few seconds to several minutes, as well as shallow breathing or complete cessation of breathing. Obstructive sleep apnea is strongly associated with the risk of developing several heart diseases, including coronary heart disease, heart attack, heart failure, and stroke. In addition, obstructive sleep apnea increases the risk of developing irregular heartbeats (arrhythmias), which can lead to low blood pressure. To prevent these conditions, this study presents a novel machine-learning (ML) model for predicting sleep apnea based on electronic health data that provides accurate predictions and helps in identifying the risk factors that contribute to the development of sleep apnea. The dataset used in the study includes 75 features and 10,765 samples from the Swedish National Study on Aging and Care (SNAC). The proposed model is based on two modules: the XGBoost module assesses the most important features from feature space, while the Bidirectional Long Short-Term Memory Networks (BiLSTM) module classifies the probability of sleep apnea. Using a cross-validation scheme, the proposed XGBoost_BiLSTM algorithm achieves an accuracy of 97% while using only the six most significant features from the dataset. The model’s performance is also compared with conventional long-short-term memory networks (LSTM) and other state-of-the-art ML models. The results of the study suggest that the proposed model improved the diagnosis and treatment of sleep apnea by identifying the risk factors.
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24. |
- Bäcklund, Nils, et al.
(author)
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Salivary cortisol and cortisone in diagnosis of Cushing's syndrome - a comparison of six different analytical methods
- 2023
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In: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter. - 1434-6621 .- 1437-4331. ; 61:10, s. 1780-1791
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Journal article (peer-reviewed)abstract
- Objectives: Salivary cortisol and cortisone at late night and after dexamethasone suppression test (DST) are increasingly used for screening of Cushing's syndrome (CS). We aimed to establish reference intervals for salivary cortisol and cortisone with three liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques and for salivary cortisol with three immunoassays (IAs), and evaluate their diagnostic accuracy for CS.Methods: Salivary samples at 08:00 h, 23:00 h and 08:00 h after a 1-mg DST were collected from a reference population (n=155) and patients with CS (n=22). Sample aliquots were analyzed by three LC-MS/MS and three IA methods. After establishing reference intervals, the upper reference limit (URL) for each method was used to calculate sensitivity and specificity for CS. Diagnostic accuracy was evaluated by comparing ROC curves.Results: URLs for salivary cortisol at 23:00 h were similar for the LC-MS/MS methods (3.4-3.9 nmol/L), but varied between IAs: Roche (5.8 nmol/L), Salimetrics (4.3 nmol/L), Cisbio (21.6 nmol/L). Corresponding URLs after DST were 0.7-1.0, and 2.4, 4.0 and 5.4 nmol/L, respectively. Salivary cortisone URLs were 13.5-16.6 nmol/L at 23:00 h and 3.0-3.5 nmol/L at 08:00 h after DST. All methods had ROC AUCs =0.96.Conclusions: We present robust reference intervals for salivary cortisol and cortisone at 08:00 h, 23:00 h and 08:00 h after DST for several clinically used methods. The similarities between LC-MS/MS methods allows for direct comparison of absolute values. Diagnostic accuracy for CS was high for all salivary cortisol and cortisone LC-MS/MS methods and salivary cortisol IAs evaluated.
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25. |
- Ahlander, Britt-Marie, 1954-
(author)
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Magnetic Resonance Imaging of the Heart : Image quality, measurement accuracy and patient experience
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Background: Non-invasive diagnostic imaging of atherosclerotic coronary artery disease (CAD) is frequently carried out with cardiovascular magnetic resonance imaging (CMR) or myocardial perfusion single photon emission computed tomography (MPS). CMR is the gold standard for the evaluation of scar after myocardial infarction and MPS the clinical gold standard for ischemia. Magnetic Resonance Imaging (MRI) is at times difficult for patients and may induce anxiety while patient experience of MPS is largely unknown.Aims: To evaluate image quality in CMR with respect to the sequences employed, the influence of atrial fibrillation, myocardial perfusion and the impact of patient information. Further, to study patient experience in relation to MRI with the goal of improving the care of these patients.Method: Four study designs have been used. In paper I, experimental cross-over, paper (II) experimental controlled clinical trial, paper (III) psychometric crosssectional study and paper (IV) prospective intervention study. A total of 475 patients ≥ 18 years with primarily cardiac problems (I-IV) except for those referred for MRI of the spine (III) were included in the four studies.Result: In patients (n=20) with atrial fibrillation, a single shot steady state free precession (SS-SSFP) sequence showed significantly better image quality than the standard segmented inversion recovery fast gradient echo (IR-FGRE) sequence (I). In first-pass perfusion imaging the gradient echo-echo planar imaging sequence (GREEPI) (n=30) had lower signal-to-noise and contrast–to-noise ratios than the steady state free precession sequence (SSFP) (n=30) but displayed a higher correlation with the MPS results, evaluated both qualitatively and quantitatively (II). The MRIAnxiety Questionnaire (MRI-AQ) was validated on patients, referred for MRI of either the spine (n=193) or the heart (n=54). The final instrument had 15 items divided in two factors regarding Anxiety and Relaxation. The instrument was found to have satisfactory psychometric properties (III). Patients who prior CMR viewed an information video scored significantly (lower) better in the factor Relaxation, than those who received standard information. Patients who underwent MPS scored lower on both factors, Anxiety and Relaxation. The extra video information had no effect on CMR image quality (IV).Conclusion: Single shot imaging in atrial fibrillation produced images with less artefact than a segmented sequence. In first-pass perfusion imaging, the sequence GRE-EPI was superior to SSFP. A questionnaire depicting anxiety during MRI showed that video information prior to imaging helped patients relax but did not result in an improvement in image quality.
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26. |
- Fromentin, S., et al.
(author)
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Microbiome and metabolome features of the cardiometabolic disease spectrum
- 2022
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:2, s. 303-314
-
Journal article (peer-reviewed)abstract
- By studying individuals along a spectrum of cardiometabolic disease and adjusting for effects of lifestyle and medication, this investigation identifies alterations of the metabolome and microbiome from dysmetabolic conditions, such as obesity and type 2 diabetes, to ischemic heart disease. Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.
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27. |
- Björkman, Kristoffer, et al.
(author)
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Genotype-phenotype correlations in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1
- 2014
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In: Euromit 2014, 15-19 juni, Tampere, Finland.
-
Conference paper (other academic/artistic)abstract
- Objectives: To study genotype-phenotype correlations in genes encoding complex I electron input module subunits. Materials and methods: We studied five patients with isolated complex I deficiency, three with NDUFS1 mutations and two with NDUFV1 mutations. A literature review of all reported cases of mutations in the affected genes was performed. Results: The literature review revealed pathological mutations in NDUFS1 for 18 patients in 17 families and correspondingly in NDUFV1 for 26 patients in 19 families. Unpublished clinical data for our five patients were added. Our study showed quite variable clinical courses; death before two years of age was seen in 41% of patients while 18% were alive at seven years. There was a significant difference between the NDUFS1 and NDUFV1 groups for clinical onset and life-span. Mutations in NDUFS1 were linked to a worse clinical course with earlier onset and earlier death. Conclusions: Genotype-phenotype correlations in patients with mutations affecting the genes that encode the electron input module of complex I vary, but patients with NDUFS1 mutation tend to have a worse clinical course than patients with NDUFV1 mutation. Identifying the mutations is of importance for accurate prognostic information and genetic counseling.
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28. |
- Hartvigsson, Olle, 1991, et al.
(author)
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Differences between Arterial and Venous Umbilical Cord Plasma Metabolome and Association with Parity
- 2022
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In: Metabolites. - : MDPI AG. - 2218-1989 .- 2218-1989. ; 12:2
-
Journal article (peer-reviewed)abstract
- Umbilical cord blood is frequently used in health monitoring of the neonate. Results may be affected by the proportion of arterial and venous cord blood, the venous blood coming from the mother to supply oxygen and nutrients to the infant, and the arterial carrying waste products from the fetus. Here, we sampled arterial and venous umbilical cords separately from 48 newly delivered infants and examined plasma metabolomes using GC-MS/MS metabolomics. We investigated differences in metabolomes between arterial and venous blood and their associations with gestational length, birth weight, sex, and whether the baby was the first born or not, as well as maternal age and BMI. Using multilevel random forest analysis, a classification rate of 79% was achieved for arteriovenous differences (p = 0.004). Several monosaccharides had higher concentrations in the arterial cord plasma while amino acids were higher in venous plasma, suggesting that the main differences in the measured arterial and venous plasma metabolomes are related to amino acid and energy metabolism. Venous cord plasma metabolites related to energy metabolism were positively associated with parity (77% classification rate, p = 0.004) while arterial cord plasma metabolites were not. This underlines the importance of defining cord blood type for metabolomic studies.
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29. |
- Ahlander, Britt-Marie, 1954-, et al.
(author)
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An echo-planar imaging sequence is superior to a steady-state free precession sequence for visual as well as quantitative assessment of cardiac magnetic resonance stress perfusion
- 2017
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In: Clinical Physiology and Functional Imaging. - : Blackwell Publishing. - 1475-0961 .- 1475-097X. ; 37:1, s. 52-61
-
Journal article (peer-reviewed)abstract
- BACKGROUND: To assess myocardial perfusion, steady-state free precession cardiac magnetic resonance (SSFP, CMR) was compared with gradient-echo-echo-planar imaging (GRE-EPI) using myocardial perfusion scintigraphy (MPS) as reference.METHODS: Cardiac magnetic resonance perfusion was recorded in 30 patients with SSFP and in another 30 patients with GRE-EPI. Timing and extent of inflow delay to the myocardium was visually assessed. Signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated. Myocardial scar was visualized with a phase-sensitive inversion recovery sequence (PSIR). All scar positive segments were considered pathologic. In MPS, stress and rest images were used as in clinical reporting. The CMR contrast wash-in slope was calculated and compared with the stress score from the MPS examination. CMR scar, CMR perfusion and MPS were assessed separately by one expert for each method who was blinded to other aspects of the study.RESULTS: Visual assessment of CMR had a sensitivity for the detection of an abnormal MPS at 78% (SSFP) versus 91% (GRE-EPI) and a specificity of 58% (SSFP) versus 84% (GRE-EPI). Kappa statistics for SSFP and MPS was 0·29, for GRE-EPI and MPS 0·72. The ANOVA of CMR perfusion slopes for all segments versus MPS score (four levels based on MPS) had correlation r = 0·64 (SSFP) and r = 0·96 (GRE-EPI). SNR was for normal segments 35·63 ± 11·80 (SSFP) and 17·98 ± 8·31 (GRE-EPI), while CNR was 28·79 ± 10·43 (SSFP) and 13·06 ± 7·61 (GRE-EPI).CONCLUSION: GRE-EPI displayed higher agreement with the MPS results than SSFP despite significantly lower signal intensity, SNR and CNR.
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30. |
- Alaridah, Nader, et al.
(author)
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Transmission dynamics study of tuberculosis isolates with whole genome sequencing in southern Sweden
- 2019
-
In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
-
Journal article (peer-reviewed)abstract
- Epidemiological contact tracing complemented with genotyping of clinical Mycobacterium tuberculosis isolates is important for understanding disease transmission. In Sweden, tuberculosis (TB) is mostly reported in migrant and homeless where epidemiologic contact tracing could pose a problem. This study compared epidemiologic linking with genotyping in a low burden country. Mycobacterium tuberculosis isolates (n = 93) collected at Scania University Hospital in Southern Sweden were analysed with the standard genotyping method mycobacterial interspersed repetitive units-variable number tandem repeats (MIRU-VNTR) and the results were compared with whole genome sequencing (WGS). Using a maximum of twelve single nucleotide polymorphisms (SNPs) as the upper threshold of genomic relatedness noted among hosts, we identified 18 clusters with WGS comprising 52 patients with overall pairwise genetic maximum distances ranging from zero to nine SNPs. MIRU-VNTR and WGS clustered the same isolates, although the distribution differed depending on MIRU-VNTR limitations. Both genotyping techniques identified clusters where epidemiologic linking was insufficient, although WGS had higher correlation with epidemiologic data. To summarize, WGS provided better resolution of transmission than MIRU-VNTR in a setting with low TB incidence. WGS predicted epidemiologic links better which could consolidate and correct the epidemiologically linked cases, avoiding thus false clustering.
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31. |
- Anderson, Jenna
(author)
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Development and evaluation of a subunit DIVA vaccine against bluetongue virus serotype 8 in cattle
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Bluetongue virus (BTV) causes the primarily vector-borne bluetongue disease of ruminants, which poses a permanent threat to Europe since new serotypes and strains are frequently introduced. Vaccination of cattle is essential to control BTV outbreaks. Commercial attenuated and inactivated vaccines are efficacious in reducing BTV spread and disease, but do not fulfil all safety, adaptability, or production requirements. Additionally, no current vaccines allow the differentiation of infected from vaccinated animals (DIVA). DIVA vaccines enable surveillance of BTV epidemiology and vaccine efficacy, and facilitate a quick return for countries to a BTV-free status. This thesis presents the development and evaluation of a novel subunit DIVA vaccine against BTV serotype 8 (BTV-8) in cattle. Five His-tagged recombinant BTV proteins (VP2, VP5 of BTV-8; NS1, NS2, NS3 of BTV-2) were produced in baculovirus or E. coli expression systems. Purification protocols were optimized for all but VP5. Based on the feasibility of protein production and the capability of the remaining four proteins to induce humoral or cellular immune responses in mice, VP2, NS1, and NS2 were selected to formulate an experimental vaccine combined to an ISCOM-matrix adjuvant (SubV). Next, cattle were immunized twice at a three-week interval with SubV, a commercial inactivated vaccine, or a placebo. SubV induced humoral immune responses, including virus-neutralizing antibodies, against all three proteins, as well as a cellular immune response directed against NS1. These responses were of similar type and comparable magnitude between both vaccines, suggesting that SubV might provide protection that is at least as effective as the commercial vaccine. Finally, the protective efficacy of SubV was evaluated and complete virological and clinical protection against virulent BTV-8 challenge was observed following vaccination in calves. This was likely due to the induction of virus-neutralizing antibodies directed against VP2 of BTV-8 and cross-serotype T cell responses directed against NS1 and NS2 of BTV-2. Furthermore, SubV was shown to be DIVA-compliant based on the detection of antibodies directed against VP7, by using commercially-available diagnostic assays. This novel BTV subunit vaccine is a promising candidate and should be further developed.
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32. |
- Lundin, Anna-Carin
(author)
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Tendinosis in Trigger Finger
- 2017
-
Doctoral thesis (other academic/artistic)abstract
- Trigger finger is one of the most common hand conditions, with a prevalence of almost 3%. The aetiology remains unclear even though many causes have been suggested. The prevailing paradigm is that the pathogenesis of trigger finger is ascribed to primary changes in the first fibrous condensation of the tendon sheath (A1-pulley). Several studies have investigated pathology in the pulley, but few have investigated the tendon. The general aim of this thesis was to find out if there is pathology in the trigger finger tendon and to define it.We first looked at trigger finger tendon biopsies in a light microscope, and found that they were histologically different from healthy tendons. They showed signs of micro-ruptures, collagen degradation, increased amounts of ground substance, both hyper- and hypo-cellular areas, round active cell nuclei and absence of inflammatory cells, all similar to tendinosis. The histological picture was further assessed by using a scoring system for Achilles tendinosis. The trigger finger tendons scored high, suggesting a similar histopathology.Next, we performed a quantitative real-time polymerase chain reaction (qPCR) on trigger finger tendons. We assessed the mRNA expression of 10 genes, which have been described to be differently expressed in Achilles tendinosis (collagen 1 and 3, versican, decorin, biglycan, aggrecan, MMP-2, MMP-3, ADAMTS-5, and TIMP-3). The overall expression pattern agreed with previous studies on Achilles tendinosis, suggesting that the cellular function in trigger finger tendons is disturbed in a similar way as in Achilles tendinosis.Recent experimental and observational research has suggested potential side effects of statin treatment on tendons, but firm evidence was lacking. We performed an epidemiological study on two large population-based cohorts. Statin use was found to increase the risk of both trigger finger and tendinosis in the shoulder and Achilles tendons, especially among men. This suggests a similar pathology in trigger finger and tendinosis.We have also studied the time to treatment effect after a single injection of glucocorticoid in trigger finger. Our results suggest that 60-80% of patients can expect resolution of the triggering within 14 days, and half of them within seven days. This result allows correct information to be given to the patient and proper planning of follow-ups.In conclusion, the pathology in trigger finger tendons is similar to tendinosis in other tendons.
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33. |
- Paterson, R W, et al.
(author)
-
A targeted proteomic multiplex CSF assay identifies increased malate dehydrogenase and other neurodegenerative biomarkers in individuals with Alzheimer's disease pathology.
- 2016
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In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 6:11
-
Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is the most common cause of dementia. Biomarkers are required to identify individuals in the preclinical phase, explain phenotypic diversity, measure progression and estimate prognosis. The development of assays to validate candidate biomarkers is costly and time-consuming. Targeted proteomics is an attractive means of quantifying novel proteins in cerebrospinal and other fluids, and has potential to help overcome this bottleneck in biomarker development. We used a previously validated multiplexed 10-min, targeted proteomic assay to assess 54 candidate cerebrospinal fluid (CSF) biomarkers in two independent cohorts comprising individuals with neurodegenerative dementias and healthy controls. Individuals were classified as 'AD' or 'non-AD' on the basis of their CSF T-tau and amyloid Aβ1-42 profile measured using enzyme-linked immunosorbent assay; biomarkers of interest were compared using univariate and multivariate analyses. In all, 35/31 individuals in Cohort 1 and 46/36 in Cohort 2 fulfilled criteria for AD/non-AD profile CSF, respectively. After adjustment for multiple comparisons, five proteins were elevated significantly in AD CSF compared with non-AD CSF in both cohorts: malate dehydrogenase; total APOE; chitinase-3-like protein 1 (YKL-40); osteopontin and cystatin C. In an independent multivariate orthogonal projection to latent structures discriminant analysis (OPLS-DA), these proteins were also identified as major contributors to the separation between AD and non-AD in both cohorts. Independent of CSF Aβ1-42 and tau, a combination of these biomarkers differentiated AD and non-AD with an area under curve (AUC)=0.88. This targeted proteomic multiple reaction monitoring (MRM)-based assay can simultaneously and rapidly measure multiple candidate CSF biomarkers. Applying this technique to AD we demonstrate differences in proteins involved in glucose metabolism and neuroinflammation that collectively have potential clinical diagnostic utility.
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34. |
- Ognissanti, Damiano, et al.
(author)
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Estimating Analytical Errors of Glomerular Filtration Rate Measurement
- 2022
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In: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 68:9, s. 1211-1218
-
Journal article (peer-reviewed)abstract
- Background Few studies are available on how to optimize time points for sampling and how to estimate effects of analytical uncertainty when glomerular filtration rate (GFR) is calculated. Methods We explored the underlying regression mathematics of how analytical variation of a kidney filtration marker affects 1-compartment, slope-and-intercept GFR calculations, using 2 or 3 time points following a bolus injection, and used this to examine the results from 731 routine 3-point iohexol plasma clearance measurements. Results GFR calculations inflated analytical uncertainty if the time points were taken too late after the bolus injection and too close after each other. The uncertainty in GFR calculation was, however, the same as the analytical uncertainty if optimal time points were used. The middle of the 3 samples was of little value. The first sample should be taken as early as possible after the distribution phase. Sampling before the patient specific half-life of the kidney filtration marker resulted in an exponential error inflation whereas no error inflation was seen when sampling occurred later than 2 half-lives. Theoretical GFR uncertainty could be lowered 2.6-fold if individually optimized time points for sampling had been used in our 731 clearance measurements. Using Taylor expansions to approximate the moments of transformed random variables, the uncertainty of an individual GFR measurement could be calculated in a simple enough way to be applicable by laboratory software. Conclusions We provide a theoretical foundation to select patient-optimal time points that may both limit errors and allow calculation of GFR uncertainty.
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35. |
- Karlsson, Iulia
(author)
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Cytokines as diagnostic biomarkers in canine pyometra and sepsis
- 2015
-
Doctoral thesis (other academic/artistic)abstract
- Sepsis is a syndrome with high morbidity, mortality and astronomical health care costs and it is challenging to diagnose both in humans and animals due to the lack of suitable diagnostic biomarkers. Although several types of proteins have been suggested as diagnostic biomarkers of sepsis, none of them were shown to be reliable for routine use in the clinical practice. Dogs with uterine bacterial infection called pyometra often develop sepsis and have been suggested as a natural model of sepsis. To investigate whether there is a pattern of biomarkers that can be useful to diagnose bacterial sepsis on early stages in addition to existing clinical criteria, we measured both local gene expression and serum levels of cytokines in dogs with pyometra and compared these levels with known inflammatory markers and blood clotting parameters. Serum concentrations of keratinocyte-derived chemokine (KC)-like protein and the global clot strength were significantly increased both in dogs with pyometra compared to healthy dogs and in dogs with sepsis compared to dogs without sepsis in pyometra. Moreover, the expression levels of the chemokines interleukin (IL)-8 and C-X-C motif ligand 5 (CXCL5) mRNA were significantly higher in uteri from dogs with pyometra compared to healthy dogs and in cultured stromal endometrial cells derived from uteri of healthy dogs and cocultured with LPS or pathogenic Escherichia coli compared to unstimulated cells. Although serum concentrations of IL-8, high-mobility group box 1 (HMGB1), prostaglandin F2α, IL-2, IL-15, IL-18, interferon (IFN)-γ and monocyte-macrophage colony stimulating factor (MG-CSF) were not different between dogs with or without sepsis in the presence of pyometra, some of these cytokines correlated significantly with clinical parameters such as total white blood cell count (correlated with HMGB1) and KC-like (correlated with IL-8). Measurements of serum IL-10, CXCL10, tumor necrosis factor (TNF)-α, IL-6 and IL-4 will require a more sensitive method in dogs with pyometra. Our findings suggest that KC-like, CXCL5 and IL-8 may be useful as early diagnostic biomarkers of sepsis in dogs with pyometra. Further investigation of these chemokines in sepsis may help to improve routines in sepsis diagnosis in dogs and possibly also humans.
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36. |
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37. |
- Mamontov, Eugen, 1955, et al.
(author)
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Oncogenic hyperplasia caused by combination of various factors: A decision-support software for radionuclide therapy
- 2007
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In: Workshop "Mathematical Modelling and Analysis of Cancer Invasion of Tissues", Mar 26, 2007 - Mar 30, 2007, Dundee, Scotland.
-
Conference paper (peer-reviewed)abstract
- The present work deals with the software based on the PhasTraM model [1] for oncogenic hyperplasia, the first stage of formation of any solid tumor. The work generalizes the related results of [2]-[6] and discusses application of the software for decision support in radionuclide therapy. The software capabilities to allow for combinations of various causes of oncogeny are emphasized. The causes comprise inflammation, immune dysfunction, and chronic psychological stress. The immune dysfunction is represented with hypogammaglobulenimia expressed in terms of the concentration of the immunoglobulin-G molecules. The level of chronic pychological stress is described with the concentration of the interleukin-6 molecules. The work considers how application of the software can support decisions on the specific radionuclide-therapy setting depending on the tissue-, organ-, and patient-specific data. This is illustrated by a number of numerical-simulation results, also the ones which include the effects of common and fractionation-based radionuclide-therapy modalities. A proper attention is paid to how specifically the input data can be prepared by prospective users of the software, i.e. the specialists who apply radionuclide therapy. The work also formulates a few directions for future research in connection with the features of the everyday work of the prospective users. REFERENCES: [1] E. Mamontov, K. Psiuk-Maksymowicz, A. Koptioug, 2006, Stochastic mechanics in the context of the properties of living systems, Mathl Comput. Modelling, 44(7-8) 595-607. [2] E. Mamontov, A. V. Koptioug, K. Psiuk-Maksymowicz, 2006, The minimal, phase-transition model for the cell-number maintenance by the hyperplasia-extended homeorhesis, Acta Biotheoretica, 54(2) 61-101. [3] K. Psiuk-Maksymowicz and E. Mamontov, 2006, The homeorhesis-based modelling and fast numerical analysis for oncogenic hyperplasia under radiotherapy, Mathl Comput. Modelling, Special Issue
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38. |
- Marcisauskas, Simonas, 1988, et al.
(author)
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Univariate and classification analysis reveals potential diagnostic biomarkers for early stage ovarian cancer Type 1 and Type 2
- 2019
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In: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 196, s. 57-68
-
Journal article (peer-reviewed)abstract
- Biomarkers for early detection of ovarian tumors are urgently needed. Tumors of the ovary grow within cysts and most are benign. Surgical sampling is the only way to ensure accurate diagnosis, but often leads to morbidity and loss of female hormones. The present study explored the deep proteome in well-defined sets of ovarian tumors, FIGO stage I, Type 1 (low-grade serous, mucinous, endometrioid; n = 9), Type 2 (high-grade serous; n = 9), and benign serous (n = 9) using TMT–LC–MS/MS. Data are available via ProteomeXchange with identifier PXD010939. We evaluated new bioinformatics tools in the discovery phase. This innovative selection process involved different normalizations, a combination of univariate statistics, and logistic model tree and naive Bayes tree classifiers. We identified 142 proteins by this combined approach. One biomarker panel and nine individual proteins were verified in cyst fluid and serum: transaldolase-1, fructose-bisphosphate aldolase A (ALDOA), transketolase, ceruloplasmin, mesothelin, clusterin, tenascin-XB, laminin subunit gamma-1, and mucin-16. Six of the proteins were found significant (p <.05) in cyst fluid while ALDOA was the only protein significant in serum. The biomarker panel achieved ROC AUC 0.96 and 0.57 respectively. We conclude that classification algorithms complement traditional statistical methods by selecting combinations that may be missed by standard univariate tests. Significance: In the discovery phase, we performed deep proteome analyses of well-defined histology subgroups of ovarian tumor cyst fluids, highly specified for stage and type (histology and grade). We present an original approach to selecting candidate biomarkers combining several normalization strategies, univariate statistics, and machine learning algorithms. The results from validation of selected proteins strengthen our prior proteomic and genomic data suggesting that cyst fluids are better than sera in early stage ovarian cancer diagnostics.
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39. |
- Ebbers, Tino, 1972-
(author)
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Flow Imaging: Cardiac Applications of 3D Cine Phase-Contrast MRI
- 2011
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In: Current Cardiovascular Imaging Reports. - : Springer Science and Business Media LLC. - 1941-9074 .- 1941-9066. ; 4:2, s. 127-133
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Research review (peer-reviewed)abstract
- Global and regional blood flow dynamics are of pivotal importance to cardiac function. Fluid mechanical forces can affect hemolysis and platelet aggregation, as well as myocardial remodeling. In recent years, assessment of blood flow patterns based on time-resolved, three-dimensional, three-directional phase-contrast MRI (3D cine PC MRI) has become possible and rapidly gained popularity. Initially, this technique was mainly known for its intuitive and appealing visualizations of the cardiovascular blood flow. Most recently, the technique has begun to go beyond compelling images toward comprehensive and quantitative assessment of blood flow. In this article, cardiac applications of 3D cine PC MRI data are discussed, starting with a review of the acquisition and analysis techniques, and including descriptions of promising applications of cardiac 3D cine PC MRI for the clinical evaluation of myocardial, valvular, and vascular disorders.
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40. |
- Berglund, Eva Caroline, et al.
(author)
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A Study Protocol for Validation and Implementation of Whole-Genome and -Transcriptome Sequencing as a Comprehensive Precision Diagnostic Test in Acute Leukemias
- 2022
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In: Frontiers in Medicine. - Lausanne, Switzerland : Frontiers Media SA. - 2296-858X. ; 9, s. 1-9
-
Journal article (peer-reviewed)abstract
- Background: Whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS), with the ability to provide comprehensive genomic information, have become the focal point of research interest as novel techniques that can support precision diagnostics in routine clinical care of patients with various cancer types, including hematological malignancies. This national multi-center study, led by Genomic Medicine Sweden, aims to evaluate whether combined application of WGS and WTS (WGTS) is technically feasible and can be implemented as an efficient diagnostic tool in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In addition to clinical impact assessment, a health-economic evaluation of such strategy will be performed. Methods and Analysis: The study comprises four phases (i.e., retrospective, prospective, real-time validation, and follow-up) including approximately 700 adult and pediatric Swedish AML and ALL patients. Results of WGS for tumor (90×) and normal/germline (30×) samples as well as WTS for tumors only will be compared to current standard of care diagnostics. Primary study endpoints are diagnostic efficiency and improved diagnostic yield. Secondary endpoints are technical and clinical feasibility for routine implementation, clinical utility, and health-economic impact. Discussion: Data from this national multi-center study will be used to evaluate clinical performance of the integrated WGTS diagnostic workflow compared with standard of care. The study will also elucidate clinical and health-economic impacts of a combined WGTS strategy when implemented in routine clinical care. Clinical Trial Registration: [https://doi.org/10.1186/ISRCTN66987142], identifier [ISRCTN66987142].
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41. |
- Aulin, Cecilia, 1979-
(author)
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Extracellular Matrix Based Materials for Tissue Engineering
- 2010
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Doctoral thesis (other academic/artistic)abstract
- The extracellular matrix is (ECM) is a network of large, structural proteins and polysaccharides, important for cellular behavior, tissue development and maintenance. Present thesis describes work exploring ECM as scaffolds for tissue engineering by manipulating cells cultured in vitro or by influencing ECM expression in vivo. By culturing cells on polymer meshes under dynamic culture conditions, deposition of a complex ECM could be achieved, but with low yields. Since the major part of synthesized ECM diffused into the medium the rate limiting step of deposition was investigated. This quantitative analysis showed that the real rate limiting factor is the low proportion of new proteins which are deposited as functional ECM. It is suggested that cells are pre-embedded in for example collagen gels to increase the steric retention and hence functional deposition. The possibility to induce endogenous ECM formation and tissue regeneration by implantation of growth factors in a carrier material was investigated. Bone morphogenetic protein-2 (BMP-2) is a growth factor known to be involved in growth and differentiation of bone and cartilage tissue. The BMP-2 processing and secretion was examined in two cell systems representing endochondral (chondrocytes) and intramembranous (mesenchymal stem cells) bone formation. It was discovered that chondrocytes are more efficient in producing BMP-2 compared to MSC. The role of the antagonist noggin was also investigated and was found to affect the stability of BMP-2 and modulate its effect. Finally, an injectable gel of the ECM component hyaluronan has been evaluated as delivery vehicle in cartilage regeneration. The hyaluronan hydrogel system showed promising results as a versatile biomaterial for cartilage regeneration, could easily be placed intraarticulary and can be used for both cell based and cell free therapies.
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42. |
- Andersson, Axel G, et al.
(author)
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Large difference but high correlation between creatinine and cystatin C estimated glomerular filtration rate in Mesoamerican sugarcane cutters.
- 2022
-
In: Occupational and environmental medicine. - : BMJ. - 1470-7926 .- 1351-0711. ; 79:7, s. 497-502
-
Journal article (peer-reviewed)abstract
- To explore the relationship between creatinine and cystatin C based estimated glomerular filtration rate (eGFR) in actively working sugarcane cutters.This cohort study included 458 sugarcane cutters from Nicaragua and El Salvador. Serum samples were taken before and at end of harvest seasons and analysed for creatinine and cystatin C. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas were used to calculate eGFRs based on creatinine (eGFRcr), cystatin C (eGFRcys) and both creatinine and cystatin C (eGFRcrcys) at each time point. Bland-Altman plots and paired t-tests were used to compare the difference between eGFRcr and eGFRcys, and the difference in eGFRs between before and at end of the harvest seasons.The mean eGFRcr was higher than eGFRcys in both cohorts; absolute difference 22mL/min/1.73 m2 (95%CI 21 to 23) in Nicaragua and 13mL/min/1.73 m2 (95%CI 11 to 15) in El Salvador. Correlations between eGFRcr and eGFRcys were high, with r=0.69, 0.77 and 0.67 in Nicaragua at pre-harvest, end-harvest and cross-harvest, and r=0.89, 0.89 and 0.49 in El Salvador.Creatinine increases among heat-stressed workers reflect reduced glomerular filtration as estimated using eGFRcys, a marker independent of muscle mass and metabolism. The discrepancy between eGFRcr and eGFRcys may indicate reduced glomerular filtration of larger molecules and/or systemic bias in CKD-EPI performance in this population.
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43. |
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44. |
- Aljabery, Firas
(author)
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Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data.Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome.Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases.Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.
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45. |
- Loftås, Per, 1964-
(author)
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Response to neoadjuvant treatment in rectal cancer surgery
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT.Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer.Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer.Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour.Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, specificity, and positive and negative predicted values for correct staging of positive lymph nodes was 37%, 84%, 70% and 57%. The size of the largest lymph node (4.5 mm, p=0.04) seemed to indicate presence of a tumour positive lymph node. We concluded that MRI couldn’t correctly stage patients for lymph node metastases in patients with complete response to CRT in the luminal tumour.
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46. |
- Robinson, Yohan, 1977, et al.
(author)
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Intravascular hemolysis and mean red blood cell age in athletes.
- 2006
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In: Medicine and science in sports and exercise. - : Ovid Technologies (Wolters Kluwer Health). - 0195-9131 .- 1530-0315. ; 38:3, s. 480-3
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Journal article (peer-reviewed)abstract
- Since the observation that mechanical stress causes red blood cell (RBC) destruction, foot-strike hemolysis has been used to explain sports anemia and RBC rejuvenation in athletes. Recently gained knowledge questions the importance of mechanical RBC trauma on RBC hemolysis in athletes.Male athletes (N = 90) and untrained male controls (N = 58) were investigated for aerobic performance, hematological parameters, serum erythropoietin concentration (EPO), soluble transferrin receptor concentration (sTFR), and erythrocyte aspartate aminotransferase activity (eAST).On hard floor running disciplines (HFR, N = 26, short- and long-distance runners, triathletes) showed a lower eAST (P < 0.001) and thus no younger RBC population than not on hard floor running athletes (NHFR, N = 64, cyclists, soccer players, others) or the untrained control group (N = 58). HFR had higher but still normal EPO (P < 0.01) and no higher sTFR.Because intravascular hemolysis occurs in swimmers, cyclists, and runners, and mean RBC age is not reduced in runners, mechanisms other than foot-strike hemolysis have to be considered as well. Possible reasons are intramuscular destruction, osmotic stress, and membrane lipid peroxidation caused by free radicals released by activated leukocytes. Intravascular hemolysis can even be regarded as physiological means to provide heme and proteins for muscle growth.
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47. |
- Qvarfordt, Mikaela, Doktorand, 1979-, et al.
(author)
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Bioelectrical impedance and lung function - associations with gender and central obesity : results of the EpiHealth study
- 2024
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In: BMC Pulmonary Medicine. - : BioMed Central (BMC). - 1471-2466. ; 24:1
-
Journal article (peer-reviewed)abstract
- BackgroundObesity is a major public health concern associated with various health problems, including respiratory impairment. Bioelectrical impedance (BIA) is used in health screening to assess body fat. However, there is no consensus in healthcare on how body fat should be assessed in relation to lung function. In this study, we aimed to investigate how BIA in relation to waist circumference contribute, using data from a large Swedish population study.MethodsA total of 17,097 participants (aged 45–75 years) were included in the study. The relationships between fat mass, waist circumference, and lung function were analysed using weighted quantile sum regression.ResultsIncreased fat mass was significantly associated with decreased lung function (FEV1, FVC) in both sexes. Also, the influence of trunk fat and waist circumference on FVC and FEV1 differed by sex: in males, waist circumference and trunk fat had nearly equal importance for FVC (variable weights of 0.42 and 0.41), whereas in females, trunk fat was significantly more important (variable weights 0.84 and 0.14). For FEV1, waist circumference was more important in males, while trunk fat was more significant in females (variable weights male 0.68 and 0.28 and 0.23 and 0.77 in female).ConclusionsOur results suggest that trunk fat should be considered when assessing the impact of adipose tissue on lung function and should potentially be included in the health controls.
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48. |
- Borrelli, P., et al.
(author)
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AI-based detection of lung lesions in F-18 FDG PET-CT from lung cancer patients
- 2021
-
In: Ejnmmi Physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 8:1
-
Journal article (peer-reviewed)abstract
- Background[F-18]-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET-CT) is a well-established modality in the work-up of patients with suspected or confirmed diagnosis of lung cancer. Recent research efforts have focused on extracting theragnostic and textural information from manually indicated lung lesions. Both semi-automatic and fully automatic use of artificial intelligence (AI) to localise and classify FDG-avid foci has been demonstrated. To fully harness AI's usefulness, we have developed a method which both automatically detects abnormal lung lesions and calculates the total lesion glycolysis (TLG) on FDG PET-CT.MethodsOne hundred twelve patients (59 females and 53 males) who underwent FDG PET-CT due to suspected or for the management of known lung cancer were studied retrospectively. These patients were divided into a training group (59%; n = 66), a validation group (20.5%; n = 23) and a test group (20.5%; n = 23). A nuclear medicine physician manually segmented abnormal lung lesions with increased FDG-uptake in all PET-CT studies. The AI-based method was trained to segment the lesions based on the manual segmentations. TLG was then calculated from manual and AI-based measurements, respectively and analysed with Bland-Altman plots.ResultsThe AI-tool's performance in detecting lesions had a sensitivity of 90%. One small lesion was missed in two patients, respectively, where both had a larger lesion which was correctly detected. The positive and negative predictive values were 88% and 100%, respectively. The correlation between manual and AI TLG measurements was strong (R-2 = 0.74). Bias was 42 g and 95% limits of agreement ranged from -736 to 819 g. Agreement was particularly high in smaller lesions.ConclusionsThe AI-based method is suitable for the detection of lung lesions and automatic calculation of TLG in small- to medium-sized tumours. In a clinical setting, it will have an added value due to its capability to sort out negative examinations resulting in prioritised and focused care on patients with potentially malignant lesions.
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49. |
- Fredenberg, Erik, 1979-
(author)
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Spectral Mammography with X-Ray Optics and a Photon-Counting Detector
- 2009
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Doctoral thesis (other academic/artistic)abstract
- Early detection is vital to successfully treating breast cancer, and mammography screening is the most efficient and wide-spread method to reach this goal. Imaging low-contrast targets, while minimizing the radiation exposure to a large population is, however, a major challenge. Optimizing the image quality per unit radiation dose is therefore essential. In this thesis, two optimization schemes with respect to x-ray photon energy have been investigated: filtering the incident spectrum with refractive x-ray optics (spectral shaping), and utilizing the transmitted spectrum with energy-resolved photon-counting detectors (spectral imaging). Two types of x-ray lenses were experimentally characterized, and modeled using ray tracing, field propagation, and geometrical optics. Spectral shaping reduced dose approximately 20% compared to an absorption-filtered reference system with the same signal-to-noise ratio, scan time, and spatial resolution. In addition, a focusing pre-object collimator based on the same type of optics reduced divergence of the radiation and improved photon economy by about 50%. A photon-counting silicon detector was investigated in terms of energy resolution and its feasibility for spectral imaging. Contrast-enhanced tumor imaging with a system based on the detector was characterized and optimized with a model that took anatomical noise into account. Improvement in an ideal-observer detectability index by a factor of 2 to 8 over that obtained by conventional absorption imaging was found for different levels of anatomical noise and breast density. Increased conspicuity was confirmed by experiment. Further, the model was extended to include imaging of unenhanced lesions. Detectability of microcalcifications increased no more than a few percent, whereas the ability to detect large tumors might improve on the order of 50% despite the low attenuation difference between glandular and cancerous tissue. It is clear that inclusion of anatomical noise and imaging task in spectral optimization may yield completely different results than an analysis based solely on quantum noise.
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50. |
- Decker, Ralph, 1968, et al.
(author)
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Case report of a girl with secondary amenorrhea associated with aurantiasis cutis
- 2016
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In: Hormone Research in Paediatrics. - : S. Karger AG. - 1663-2818 .- 1663-2826.
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Conference paper (other academic/artistic)abstract
- Introduction: --- Aurantiasis cutis is a condition of yellowish or golden skin discoloration that can result from eating excessive amounts of foods containing carotene leading to hypercarotenemia(1), described causing secondary amenorrhea(2). Objective & hypothesis: --- Hypercarotenemia can cause secondary amenorrhea without overconsumption of excessive quantities of carotene. Results: --- Laboratory tests showed a ß-Carotene level more than the 2-fold above the upper reference level. Hyperbilirubinemia could be excluded. Hypogonadotropic hypogonadism was not present. There was no evidence for adrenal dysfunction. Liver function tests were normal. Material/ Methods: --- A 16-year-old girl presented to our endocrine outpatient clinic with a 2-year history of varying yellow discoloration of her skin and secondary amenorrhea. The findings of the general physical examination were normal, but there was a marked yellow discoloration of the palms, soles, and nasolabial folds. A dietary history revealed a low carotene diet, but also a low carbohydrate diet. BMI was 19.9 kg/m² (-0.2 SDS) without signs of anorexia. Discussion: --- In this girl we observed hypercarotenemia associated with secondary nonhypothalamic amenorrhea in absence of excess external intake of carotenes. This suggests an intrinsic reason due to a polymorphism(3) in ß-carotene 15,15'-monooxygenase (BCO)(4), an enzyme breaking down carotenes to vitamin A(5). Phenotype-genotype association studies are needed to confirm this hypothesis. Conclusion: --- Secondary non-hypothalamic amenorrhea can be associated with hypercarotenemia. References: --- 1. Tanikawa K, Seta K, Machii A, Itoh S 1961 [Aurantiasis cutis due to overeating of dried laver (nori): a case report]. Jpn J Med Sci Biol 50:414-419 2. Kemmann E, Pasquale SA, Skaf R 1983 Amenorrhea associated with carotenemia. JAMA 249:926-929 3. Leung WC, Hessel S, Meplan C, Flint J, Oberhauser V, Tourniaire F, Hesketh JE, von Lintig J, Lietz G 2009 Two common single nucleotide polymorphisms in the gene encoding beta-carotene 15,15'-monoxygenase alter beta-carotene metabolism in female volunteers. FASEB j 23:1041-1053 4. Frumar AM, Meldrum DR, Judd HL 1979 Hypercarotenemia in hypothalamic amenorrhea. Fertil Steril 32:261-264 5. Lindqvist A, Andersson S 2002 Biochemical properties of purified recombinant human beta-carotene 15,15'-monooxygenase. J Biol Chem 277:23942-23948
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