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1.
  • Ertzgaard, Per, 1958-, et al. (författare)
  • Oculomotor screening and neuro-visual rehabilitation following pediatric brain tumor resection
  • 2023
  • Ingår i: Journal of Pediatric Rehabilitation Medicine. - : Ios press. - 1874-5393 .- 1875-8894. ; , s. 1-7
  • Tidskriftsartikel (refereegranskat)abstract
    • Visual difficulties are common after brain tumors, despite a lack of visual complaints at diagnosis. These include difficulties with eye movements, visual coordination, vergence, accommodation, and photophobia, in addition to more obvious problems such as visual field defects.This case report presents the results of a thorough neuro-visual evaluation in a boy with sequelae after a brain tumor including intermittent double vision that was not explained by routine visual examination. Subjective complaints included poor reading perseverance, intermittent blurred and double vision, headache around the eyes when performing near activities, less efficient eye movement behavior in reading tasks, and increased sensitivity to visual motion. The patient participated in a multidisciplinary visual rehabilitation program that included reading glasses with prism compensation and tinted glasses, as well as training with the aim of improving eye teaming, near vision functions, and perseverance in eye movements.The patient responded quickly to the vision therapy program, with positive changes after just four weeks. Repeated neuro-visual evaluations over eight months showed remarkable improvements that were stable over time. This encouraging case report supports the notion that neuro-visual evaluation and rehabilitation should be included in the follow-up of patients after brain tumors.
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2.
  • Petersson, Jöran, et al. (författare)
  • Teaching dimensional analysis in secondary school mathematics
  • 2021
  • Ingår i: Abstract book nofa8. - : Western Norway University of Applied Sciences.
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • AbstractIn its elementary form, the idea of dimensional analysis is to look at the unit of a magnitude, for example speed, and conclude that speed measured in m/s is a quotient having meters in the numerator and seconds in the denominator. However, despite dimensional analysis being a not un-common theme for research in mathematics education at tertiary level teaching, it seems in practice absent below that level. This is surprising since dimensional analysis is useful in mathematical problem solving involving proportionality. Even more so since, from halves and doubles in preschool to scalar multiplication in upper secondary school, proportionality permeates school mathematics and is well-researched (Lamon, 2007). Hence, the authors initiated a research project on how to teach dimensional analysis in school years 6-12. The novelty of this area made us choose didactical engineering (Artigue, 2015) as a theoretical framework suitable for developing the teaching of dimensional analysis. Accordingly, in a cycle of a priori and a posteriori analyses, the authors are developing an empirically based teaching model for dimensional analysis including the topic of constructing exercises for students. We present results from this on-going development project. ReferencesArtigue, M. (2015). Perspectives on Design Research: The Case of Didactical Engineering. In A. Bikner-Ahsbahs, C. Knipping, N. Presmeg. (Eds.). Approaches to Qualitative Research in Mathematics Education. Dordrecht: Springer.Lamon, S. J. (2007). Rational numbers and proportional reasoning: Towards a theoretical framework. In F.K. Lester (red) Second handbook of research on mathematics teaching and learning, vol 2 (pp. 629–668). Charlotte, NC: NCTM.
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3.
  • Aaltonen, H. Laura, et al. (författare)
  • Airspace dimension assessment with nanoparticles as a proposed biomarker for emphysema
  • 2021
  • Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 76:10, s. 1040-1043
  • Tidskriftsartikel (refereegranskat)abstract
    • Airspace dimension assessment with nanoparticles (AiDA) is a novel method to measure distal airspace radius non-invasively. In this study, AiDA radii were measured in 618 individuals from the population-based Swedish CArdiopulmonary BioImaging Study, SCAPIS. Subjects with emphysema detected by computed tomography were compared to non-emphysematous subjects. The 47 individuals with mainly mild-to-moderate visually detected emphysema had significantly larger AiDA radii, compared with non-emphysematous subjects (326±48 μm vs 291±36 μm); OR for emphysema per 10 μm: 1.22 (1.13-1.30, p<0.0001). Emphysema according to CT densitometry was similarly associated with larger radii compared with non-emphysematous CT examinations (316±41 μm vs 291 μm±26 μm); OR per 10 μm: 1.16 (1.08-1.24, p<0.0001). The results are in line with comparable studies. The results show that AiDA is a potential biomarker for emphysema in individuals in the general population.
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  • Andersson, Jenny, et al. (författare)
  • Patient´s description of onset stroke symptoms : Oral Presentations. ESOC 2023 Abstract Book
  • 2023
  • Ingår i: European Stroke Journal. - : Sage Publications. - 2396-9873 .- 2396-9881. ; 8:2, s. 427-427
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and aims: Stroke symptoms vary and could be hard to recognize. In addition, stroke severity has decreased according to the National Institutes of Health Stroke Scale (NISSH), with less pronounced symptoms expression. Knowledge on the patient’s description of stroke symptoms is therefore needed. The aim was to describe patient’s symptoms at stroke onset.Methods: A qualitative content analysis was used. Data were collected through individual interviews with 27 patients (16 men and 11 women, median age 70.4 years). All patients were hospitalized with a first-time stroke. The interviews were conducted within 4 weeks of symptoms onset and before hospital discharge.Results: All patients had symptoms that affected their daily life. Some patients described having multiple symptoms at the same time, others had symptoms that began insidiously and worsened over time. Symptoms such as overwhelming fatigue or nausea were described as Premonition of becoming ill, feeling unwell or that something was wrong. Motoric bodily changes were multifaceted as slurred speech or dizziness, balance difficulties and losing control of the body or motor dysfunction. But also, that the surroundings were distorted, and solid objects moved around. Symptoms of Dazed and affected senses included confusion and visual impairment or headache.Conclusions: Stroke is a complex disease with several different symptoms’ expressions and could be difficult to recognize, especially when symptoms are less typical or perceived as not serious. Increased awareness of stroke symptoms among caregivers and among members of the community is important and needed.
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6.
  • Andersson, Jenny, et al. (författare)
  • Symptoms at stroke onset as described by patients: a qualitative study
  • 2024
  • Ingår i: BMC Neurology. - : Springer Nature. - 1471-2377. ; 24:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Stroke is a common and severe disease that requires prompt care. Symptom expressions as one-sidedweakness and speech difficulties are common and included in public stroke campaigns. For some patients stroke canpresent with subtle and less common symptoms, difficult to interpret. The symptom severity assessed by the NationalInstitutes of Health Stroke Scale has decreased, and symptoms at onset may have changed. Therefore, we aimed toinvestigate how patients describe their symptoms at the onset of a first-time stroke.Methods:The study used a qualitative descriptive design and conventional content analysis. Data were collectedthrough recorded interviews with 27 patients aged 18 years and older hospitalised with a first-time stroke betweenOctober 2018 and April 2020. Data were analysed on a manifest level.Results: Symptoms at stroke onset were presented in two themes: Altered Reality and Discomfort and Changed BodyFunctions and described in five categories. Various types of symptoms were found. All symptoms were perceivedas sudden, persistent, and never experienced before and this appear as a “red thread” in the result. Regardless ofsymptom expressions, no specific symptom was described as more severe than another.Conclusions: Stroke symptoms were described with a variety of expressions. Many described complex symptomsnot typical of stroke, which can make it difficult to recognise the symptoms as a stroke and delay medical care. Publicstroke campaigns should emphasize the importance of seeking medical care at the slightest suspicion of stroke andcould be designed to help achieve this.
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7.
  • Auffret, Alistair G., et al. (författare)
  • More warm-adapted species in soil seed banks than in herb layer plant communities across Europe
  • 2023
  • Ingår i: Journal of Ecology. - : John Wiley & Sons. - 0022-0477 .- 1365-2745. ; 111:5, s. 1009-1020
  • Tidskriftsartikel (refereegranskat)abstract
    • Responses to climate change have often been found to lag behind the rate of warming that has occurred. In addition to dispersal limitation potentially restricting spread at leading range margins, the persistence of species in new and unsuitable conditions is thought to be responsible for apparent time-lags. Soil seed banks can allow plant communities to temporarily buffer unsuitable environmental conditions, but their potential to slow responses to long-term climate change is largely unknown. As local forest cover can also buffer the effects of a warming climate, it is important to understand how seed banks might interact with land cover to mediate community responses to climate change. We first related species-level seed bank persistence and distribution-derived climatic niches for 840 plant species. We then used a database of plant community data from grasslands, forests and intermediate successional habitats from across Europe to investigate relationships between seed banks and their corresponding herb layers in 2763 plots in the context of climate and land cover. We found that species from warmer climates and with broader distributions are more likely to have a higher seed bank persistence, resulting in seed banks that are composed of species with warmer and broader climatic distributions than their corresponding herb layers. This was consistent across our climatic extent, with larger differences (seed banks from even warmer climates relative to vegetation) found in grasslands. Synthesis. Seed banks have been shown to buffer plant communities through periods of environmental variability, and in a period of climate change might be expected to contain species reflecting past, cooler conditions. Here, we show that persistent seed banks often contain species with relatively warm climatic niches and those with wide climatic ranges. Although these patterns may not be primarily driven by species’ climatic adaptations, the prominence of such species in seed banks might still facilitate climate-driven community shifts. Additionally, seed banks may be related to ongoing trends regarding the spread of widespread generalist species into natural habitats, while cool-associated species may be at risk from both short- and long-term climatic variability and change. 
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  • Bauer, Susanne (författare)
  • Cell type-specific translatome analysis of mouse models of three genetic neurodegenerative diseases
  • 2023
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The burden neurodegenerative diseases place on patients, their loved ones, and the healthcare system is significant, and despite extensive research efforts, there is currently no cure. Since degenerative changes in the brain can begin years before symptoms appear, early intervention is critical. Additionally, neurodegenerative diseases target certain brain regions and neuron types early on. A more comprehensive understanding of the affected cells during the presymptomatic phase is therefore crucial for an effective and targeted intervention. Herein, we isolated, sequenced, and analyzed translatome samples from six neuronal cell types in knock-in mouse models of three monogenic neurodegenerative diseases at a presymptomatic stage: genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Huntington’s disease (HD). To obtain the translatome samples, we used RiboTag to immunoprecipitate HA-tagged ribosomes with their translating mRNAs from targeted cell types. We analyzed six cell types across two brain regions: cerebral and cerebellar glutamatergic and GABAergic neurons, and cerebral parvalbumin (PV) and somatostatin (SST)-expressing neurons. In the first paper, we focused our analysis on the prion diseases, gCJD (E200K) and FFI (D178N). Here observed a similar response of SST+ neurons, a cell type not previously reported as affected, in both disease models. This was characterized by upregulation of ribosomeassociated genes, and downregulation of cytoskeleton and synapse-associated genes in FFI. Weighted gene co-expression network analysis of SST+ neurons pointed towards the downregulation of mTOR inhibition as a potential mechanism underlying the observed gene expression changes. In the second paper, we analyzed a 129S4-HdhQ200 knock-in mouse model of HD. Histological and behavioral assessment revealed pathological changes in the striatum and cerebellum at 9 months and a later, mild behavioral phenotype. Translatome analysis indicated a surprisingly strong response in reportedly resistant glutamatergic neurons of the cerebellum, marked by upregulation of cell cycle regulators Ccnd1 and chromobox protein genes. In the third paper, we aimed to compare disease-specific responses of PV+ neurons across the three disease models. This analysis revealed a milder response in HD compared to prion disease at comparable disease stages. Functional analysis further indicated PV+ neurons may respond differently in the investigated diseases, showing upregulation of immune response-associated pathways in gCJD, neurodegenerative-disease pathways in FFI, and autophagy in HD. Lastly, the generation of mouse models such as were used in papers I-III requires stable and predictable transgene expression without interfering with the expression of endogenous genes. In the fourth paper, we conducted a pilot study to compare three potential loci, Rpl6, Rpl7, and Eef1a1, as potential safe harbors for transgene integration. Preliminary results indicated that the Rpl6 locus may be best suited for our purposes. Furthermore, this work generated a novel dataset consisting of translatome profiles of six cell types in three neurodegenerative disease models. This provides gene expression data at a previously unavailable level of cellular resolution, especially in prion disease. We believe that this data will serve as a valuable resource for future research and help expand our understanding of the early molecular mechanisms in neurodegenerative disease beyond the scope of this thesis. 
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11.
  • Bergfeldt, Nora, et al. (författare)
  • Identification of microbial pathogens in Neolithic Scandinavian humans
  • 2024
  • Ingår i: Scientific Reports. - : NATURE PORTFOLIO. - 2045-2322. ; 14
  • Tidskriftsartikel (refereegranskat)abstract
    • With the Neolithic transition, human lifestyle shifted from hunting and gathering to farming. This change altered subsistence patterns, cultural expression, and population structures as shown by the archaeological/zooarchaeological record, as well as by stable isotope and ancient DNA data. Here, we used metagenomic data to analyse if the transitions also impacted the microbiome composition in 25 Mesolithic and Neolithic hunter-gatherers and 13 Neolithic farmers from several Scandinavian Stone Age cultural contexts. Salmonella enterica, a bacterium that may have been the cause of death for the infected individuals, was found in two Neolithic samples from Battle Axe culture contexts. Several species of the bacterial genus Yersinia were found in Neolithic individuals from Funnel Beaker culture contexts as well as from later Neolithic context. Transmission of e.g. Y. enterocolitica may have been facilitated by the denser populations in agricultural contexts.
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12.
  • Bergfeldt, Nora, et al. (författare)
  • Identification of microbial pathogens in Neolithic Scandinavian humans
  • 2024
  • Ingår i: Scientific Reports. - : NATURE PORTFOLIO. - 2045-2322. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • With the Neolithic transition, human lifestyle shifted from hunting and gathering to farming. This change altered subsistence patterns, cultural expression, and population structures as shown by the archaeological/zooarchaeological record, as well as by stable isotope and ancient DNA data. Here, we used metagenomic data to analyse if the transitions also impacted the microbiome composition in 25 Mesolithic and Neolithic hunter-gatherers and 13 Neolithic farmers from several Scandinavian Stone Age cultural contexts. Salmonella enterica, a bacterium that may have been the cause of death for the infected individuals, was found in two Neolithic samples from Battle Axe culture contexts. Several species of the bacterial genus Yersinia were found in Neolithic individuals from Funnel Beaker culture contexts as well as from later Neolithic context. Transmission of e.g. Y. enterocolitica may have been facilitated by the denser populations in agricultural contexts.
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13.
  • Brattås, Per Ludvik, et al. (författare)
  • Impact of differential and time-dependent autophagy activation on therapeutic efficacy in a model of Huntington disease
  • 2021
  • Ingår i: Autophagy. - : Informa UK Limited. - 1554-8627 .- 1554-8635. ; 17:6, s. 1316-1329
  • Tidskriftsartikel (refereegranskat)abstract
    • Activation of macroautophagy/autophagy, a key mechanism involved in the degradation and removal of aggregated proteins, can successfully reverse Huntington disease phenotypes in various model systems. How neuronal autophagy impairments need to be considered in Huntington disease progression to achieve a therapeutic effect is currently not known. In this study, we used a mouse model of HTT (huntingtin) protein aggregation to investigate how different methods and timing of autophagy activation influence the efficacy of autophagy-activating treatment in vivo. We found that overexpression of human TFEB, a master regulator of autophagy, did not decrease mutant HTT aggregation. On the other hand, Becn1 overexpression, an autophagic regulator that plays a key role in autophagosome formation, partially cleared mutant HTT aggregates and restored neuronal pathology, but only when administered early in the disease progression. When Becn1 was administered at a later stage, when prominent mutant HTT accumulation and autophagy impairments have occurred, Becn1 overexpression did not rescue the mutant HTT-associated phenotypes. Together, these results demonstrate that the targets used to activate autophagy, as well as the timing of autophagy activation, are crucial for achieving efficient therapeutic effects.
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14.
  • Breton, Gwenna, et al. (författare)
  • Comparison of sequencing data processing pipelines and application to underrepresented African human populations
  • 2021
  • Ingår i: BMC Bioinformatics. - : BioMed Central (BMC). - 1471-2105. ; 22:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Population genetic studies of humans make increasing use of high-throughput sequencing in order to capture diversity in an unbiased way. There is an abundance of sequencing technologies, bioinformatic tools and the available genomes are increasing in number. Studies have evaluated and compared some of these technologies and tools, such as the Genome Analysis Toolkit (GATK) and its "Best Practices" bioinformatic pipelines. However, studies often focus on a few genomes of Eurasian origin in order to detect technical issues. We instead surveyed the use of the GATK tools and established a pipeline for processing high coverage full genomes from a diverse set of populations, including Sub-Saharan African groups, in order to reveal challenges from human diversity and stratification. Results We surveyed 29 studies using high-throughput sequencing data, and compared their strategies for data pre-processing and variant calling. We found that processing of data is very variable across studies and that the GATK "Best Practices" are seldom followed strictly. We then compared three versions of a GATK pipeline, differing in the inclusion of an indel realignment step and with a modification of the base quality score recalibration step. We applied the pipelines on a diverse set of 28 individuals. We compared the pipelines in terms of count of called variants and overlap of the callsets. We found that the pipelines resulted in similar callsets, in particular after callset filtering. We also ran one of the pipelines on a larger dataset of 179 individuals. We noted that including more individuals at the joint genotyping step resulted in different counts of variants. At the individual level, we observed that the average genome coverage was correlated to the number of variants called. Conclusions We conclude that applying the GATK "Best Practices" pipeline, including their recommended reference datasets, to underrepresented populations does not lead to a decrease in the number of called variants compared to alternative pipelines. We recommend to aim for coverage of > 30X if identifying most variants is important, and to work with large sample sizes at the variant calling stage, also for underrepresented individuals and populations.
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15.
  • Breton, Gwenna (författare)
  • Human demographic history : Insights on the human past based on genomes from Southern through Central Africa
  • 2020
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Evidence from paleontology, archaeology and population genetics support that modern humans originated in Africa. While the out-of-Africa event and subsequent colonization of all continents are well documented, human history in Africa at that time and before is less studied. Some current-day hunter-gatherer populations trace most of their genetic lineages to populations who inhabited Sub-Saharan Africa until the arrival of farming. They are informative about human history before and after the arrival of farming.I studied high-coverage genomes from two such groups, the Khoe-San from Southern Africa and the rainforest hunter-gatherers from Central Africa. I generated a total of 74 genomes, significantly increasing the number of genomes from Sub-Saharan African hunter-gatherers. I compared several versions of a commonly used pipeline for high-coverage genomes and showed that using standard ascertained reference datasets has no significant impact on variant calling in populations from Sub-Saharan Africa. Using the full genome information, I described the genetic diversity in the Khoe-San and in the rainforest hunter-gatherers and showed that gene flow from agropastoralist groups increased the Khoe-San genetic diversity. I also detected a signal of population size decline in the Khoe-San around the time of the out-of-Africa event, and I evaluated the power of the method to detect bottlenecks by applying it to simulated data. I investigated the history of modern humans in Africa by estimating divergence times between populations and applying an Approximate Bayesian Computation analysis. We confirmed that the earliest divergence event was between the Khoe-San ancestral lineage and the rest of modern humans, ~250-350 kya. I also showed that the possibility of high gene flow should be incorporated in models of human evolution.I furthermore examined SNP array data for two BaTwa populations from Zambia and showed that 20-30% of their autosomal diversity is hunter-gatherer-like. The estimated times for the admixture between a presumably local hunter-gatherer population and incoming agropastoralist groups are consistent with archaeological records.In this thesis, I investigated questions related to human history in Sub-Saharan Africa, from the emergence of modern humans ~300 kya to recent events related to the expansion of farming.
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16.
  • Chen, Ziqing, et al. (författare)
  • Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25(+)/CD54(+) NK cells
  • 2021
  • Ingår i: EMBO Reports. - : EMBO Press. - 1469-221X .- 1469-3178. ; 22:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Inadequate persistence of tumor-infiltrating natural killer (NK) cells is associated with poor prognosis in cancer patients. The solid tumor microenvironment is characterized by the presence of immunosuppressive factors, including prostaglandin E2 (PGE2), that limit NK cell persistence. Here, we investigate if the modulation of the cytokine environment in lung cancer with IL-2 or IL-15 renders NK cells resistant to suppression by PGE2. Analyzing Cancer Genome Atlas (TCGA) data, we found that high NK cell gene signatures correlate with significantly improved overall survival in patients with high levels of the prostaglandin E synthase (PTGES). In vitro, IL-15, in contrast to IL-2, enriches for CD25(+)/CD54(+) NK cells with superior mTOR activity and increased expression of the cAMP hydrolyzing enzyme phosphodiesterase 4A (PDE4A). Consequently, this distinct population of NK cells maintains their function in the presence of PGE2 and shows an increased ability to infiltrate lung adenocarcinoma tumors in vitro and in vivo. Thus, strategies to enrich CD25(+)/CD54(+) NK cells for adoptive cell therapy should be considered.
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  • Eklund, Andreas, et al. (författare)
  • Development and evaluation of the MAINTAIN instrument, selecting patients suitable for secondary or tertiary preventive manual care : the Nordic maintenance care program
  • 2022
  • Ingår i: Chiropractic and Manual Therapies. - : Springer Science and Business Media LLC. - 2045-709X. ; 30:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Chiropractic maintenance care (MC) has been found to be effective for patients classified as dysfunctional by the West Haven-Yale Multidimensional Pain Inventory (MPI). Although displaying good psychometric properties, the instrument was not designed to be used in clinical practice to screen patients for stratified care pathways. The aim was to develop a brief clinical instrument with the intent of identifying dysfunctional patients with acceptable diagnostic accuracy. Methods: Data from 249 patients with a complete MPI dataset from a randomized clinical trial that investigated the effect and cost-effectiveness of MC with a 12-month follow-up was used in this cross-sectional analysis. A brief screening instrument was developed to identify dysfunctional patients, with a summary measure. Different cut-offs were considered with regards to diagnostic accuracy using the original instrument’s classification of dysfunctional patients as a reference. Very good diagnostic accuracy was defined as an area under the curve (AUC) metric between 0.8 and 0.9. The instrument was then externally validated in 3 other existing datasets to assess model transportability across populations and medical settings. Results: Using an explorative approach, the MAINTAIN instrument with 10 questions (0–6 Likert responses) capturing 5 dimensions (pain severity, interference, life control, affective distress, and support) was developed, generating an algorithm-based score ranging from − 12 to 48. Reporting a MAINTAIN score of 18 or higher, 146 out of the 249 patients were classified as dysfunctional with 95.8% sensitivity and 64.3% specificity. At a score of 22 or higher, 109/249 were classified as dysfunctional with 81.1% sensitivity and 79.2% specificity. AUC was estimated to 0.87 (95% CI 0.83, 0.92) and Youden’s index was highest (0.70) at a score of 20. The diagnostic accuracy was similar and high across populations with minor differences in optimal thresholds for identifying dysfunctional individuals. Conclusion: The MAINTAIN instrument has very good diagnostic accuracy with regards to identifying dysfunctional patients and may be used as a decision aid in clinical practice. By using 2 thresholds, patients can be categorized into “low probability (− 12 to 17)”, “moderate probability (18 to 21)”, and “high probability (22 to 48)” of having a good outcome from maintenance care for low back pain. Trial registration: Clinical trials.gov; NCT01539863; registered February 28, 2012; https://clinicaltrials.gov/ct2/show/NCT01539863.
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20.
  • Emmerich, Anne C., et al. (författare)
  • Proteomics-Based Characterization of miR-574-5p Decoy to CUGBP1 Suggests Specificity for mPGES-1 Regulation in Human Lung Cancer Cells
  • 2020
  • Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • MicroRNAs (miRs) are one of the most important post-transcriptional repressors of gene expression. However, miR-574-5p has recently been shown to positively regulate the expression of microsomal prostaglandin E-synthase-1 (mPGES-1), a key enzyme in the prostaglandin E2 (PGE2) biosynthesis, by acting as decoy to the RNA-binding protein CUG-RNA binding protein 1 (CUGBP1) in human lung cancer. miR-574-5p exhibits oncogenic properties and promotes lung tumor growth in vivo via induction of mPGES-1-derived PGE2 synthesis. In a mass spectrometry-based proteomics study, we now attempted to characterize this decoy mechanism in A549 lung cancer cells at a cellular level. Besides the identification of novel CUGBP1 targets, we identified that the interaction between miR-574-5p and CUGBP1 specifically regulates mPGES-1 expression. This is supported by the fact that CUGBP1 and miR-574-5p are located in the nucleus, where CUGBP1 regulates alternative splicing. Further, in a bioinformatical approach we showed that the decoy-dependent mPGES-1 splicing pattern is unique. The specificity of miR-574-5p/CUGBP1 regulation on mPGES-1 expression supports the therapeutic strategy of pharmacological inhibition of PGE2 formation, which may provide significant therapeutic value for NSCLC patients with high miR-574-5p levels.
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21.
  • Fischer, Per, 1981-, et al. (författare)
  • Total Wrist Arthroplasty : A 10-Year Follow-Up
  • 2020
  • Ingår i: Journal of Hand Surgery-American Volume. - : Elsevier. - 0363-5023 .- 1531-6564. ; 45:8, s. 780.e1-780.e10
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To assess long-term implant survival in total wrist arthroplasty (TWA), comparing 4 different implants.Methods: In a prospective cohort of 124 patients, 136 TWAs were evaluated 5 years and 10 years after surgery. The TWAs were implanted between 2005 and 2009. The primary outcome was implant survival. Survival analysis was performed with revision and radiographic loosening as the final end point. Revision was defined as exchange of whole or parts of the prosthesis. Implant loosening was assessed using radiographic examination at the 5-year and 10-year follow-up. Secondary outcome measures included wrist range of motion, hand grip strength, visual analog scale (VAS) pain scores, and patient-related outcome measures, including Disabilities of the Arm, Shoulder, and Hand (DASH), Patient-Rated Wrist Evaluation (PRWE), and Canadian Occupational Performance Measure (COPM).Results: Total cumulative implant survival was 92% with revision as the primary end point. When including a nonrevised radiographic loose implant as a failure, total implant survival was 75%. Radiographic loosening differed significantly between the implants with a range in frequency from 0% to 37.5%. At the 10-year follow-up, assessing the nonrevised TWAs, range of motion was preserved compared with preoperative values. Significant improvement was recorded for hand grip strength, VAS pain scores, and patient-related outcome measures at the 10-year follow-up compared with preovperative values.Conclusions: High 10-year implant survival was found when defining the primary end point as revision of any cause. When including radiographic loosening of the implant in the survival analysis, implant survival was considerably lower. However, radiographic loosening does not seem to correlate with changes in secondary outcome measures, questioning the need for revision surgery in these cases.
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  • Galindo-Feria, Angeles S., et al. (författare)
  • Proinflammatory Histidyl-Transfer RNA Synthetase-Specific CD4+T Cells in the Blood and Lungs of Patients With Idiopathic Inflammatory Myopathies
  • 2020
  • Ingår i: Arthritis & Rheumatology. - : WILEY. - 2326-5191 .- 2326-5205. ; 72:1, s. 179-191
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Autoantibodies targeting histidyl-transfer RNA synthetase (HisRS; anti-Jo-1) are common in the idiopathic inflammatory myopathies (IIMs) and antisynthetase syndrome. This study was undertaken to investigate immunity against HisRS in the blood and lungs of patients with IIM/antisynthetase syndrome. Methods Bronchoalveolar lavage (BAL) fluid, BAL fluid cells, and peripheral blood mononuclear cells (PBMCs) from patients with IIM/antisynthetase syndrome (n = 24) were stimulated with full-length HisRS protein or a HisRS-derived peptide (HisRS(11-23)). BAL fluid and PBMCs from patients with sarcoidosis (n = 7) and healthy subjects (n = 12) were included as controls. The CD4+ T cell response was determined according to levels of CD40L up-regulation and cytokine expression using flow cytometry. Anti-Jo-1 autoantibody responses in the serum and BAL fluid were assessed by enzyme-linked immunosorbent assay. Lung biopsy samples from patients with IIM/antisynthetase syndrome (n = 14) were investigated by immunohistochemistry. Results In BAL fluid, CD4+ T cells from 3 of 4 patients with IIM/antisynthetase syndrome responded to stimulation with HisRS protein, as measured by the median fold change in CD40L expresssion in stimulated cells compared to unstimulated cells (median fold change 3.6, interquartile range [IQR] 2.7-14.7), and 2 of 3 patients with IIM/antisynthetase syndrome had the highest responses to HisRS(11-23) (median fold change 88, IQR 27-149)(.) In PBMCs, CD4+ T cells from 14 of 18 patients with IIM/antisynthetase syndrome responded to HisRS protein (median fold change 7.38, IQR 2.69-31.86; P < 0.001), whereas a HisRS(11-23) response was present in 11 of 14 patients with IIM/antisynthetase syndrome (median fold change 3.4, IQR 1.87-10.9; P < 0.001). In the control group, there was a HisRS(11-23) response in 3 of 7 patients with sarcoidosis (median fold change 2.09, IQR 1.45-3.29) and in 5 of 12 healthy controls (median fold change 2, IQR 1.89-2.42). CD4+ T cells from patients with IIM/antisynthetase syndrome displayed a pronounced Th1 phenotype in the BAL fluid when compared to the PBMCs (P < 0.001), producing high amounts of interferon-gamma and interleukin-2 following stimulation. Anti-Jo-1 autoantibodies were detected in BAL fluid and germinal center (GC)-like structures were seen in the lung biopsy samples from patients with IIM/antisynthetase syndrome. Conclusion The results of this study demonstrate a pronounced presence of HisRS-reactive CD4+ T cells in PBMCs and BAL fluid cells from patients with IIM/antisynthetase syndrome as compared to patients with sarcoidosis and healthy controls. These findings, combined with the presence of anti-Jo-1 autoantibodies in BAL fluid and GC-like structures in the lungs, suggest that immune activation against HisRS might take place within the lungs of patients with IIM/antisynthetase syndrome.
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23.
  • Grassi, Daniela A., et al. (författare)
  • Profiling of lincRNAs in human pluripotent stem cell derived forebrain neural progenitor cells
  • 2020
  • Ingår i: Heliyon. - : Elsevier BV. - 2405-8440. ; 6:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) can be differentiated into many different cell types of the central nervous system. One challenge when using pluripotent stem cells is to develop robust and efficient differentiation protocols that result in homogenous cultures of the desired cell type. Here, we have utilized the SMAD-inhibitors SB431542 and Noggin in a fully defined monolayer culture model to differentiate human pluripotent cells into homogenous forebrain neural progenitors. Temporal fate analysis revealed that this protocol results in forebrain-patterned neural progenitor cells that start to express early neuronal markers after two weeks of differentiation, allowing for the analysis of gene expression changes during neurogenesis. Using this system, we were able to identify many previously uncharacterized long intergenic non-coding RNAs that display dynamic expression during human forebrain neurogenesis. Cell biology; Genetics; Neuroscience; Developmental genetics; Cellular neuroscience; lincRNAs; Forebrain development; Induced pluripotent stem cells; Neural progenitor cells; Differentiation
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24.
  • Grigoriou, Sotirios, et al. (författare)
  • Comparison of dyskinesia profiles after L-DOPA dose challenges with or without dopamine agonist coadministration
  • 2023
  • Ingår i: Neuropharmacology. - 0028-3908. ; 237
  • Tidskriftsartikel (refereegranskat)abstract
    • Many patients with Parkinson's disease (PD) experiencing L-DOPA-induced dyskinesia (LID) receive adjunct treatment with dopamine agonists, whose functional impact on LID is unknown. We set out to compare temporal and topographic profiles of abnormal involuntary movements (AIMs) after L-DOPA dose challenges including or not the dopamine agonist ropinirole. Twenty-five patients with PD and a history of dyskinesias were sequentially administered either L-DOPA alone (150% of usual morning dose) or an equipotent combination of L-DOPA and ropinirole in random order. Involuntary movements were assessed by two blinded raters prior and every 30 min after drug dosing using the Clinical Dyskinesia Rating Scale (CDRS). A sensor-recording smartphone was secured to the patients' abdomen during the test sessions. The two raters’ CDRS scores were highly reliable and concordant with models of hyperkinesia presence and severity trained on accelerometer data. The dyskinesia time curves differed between treatments as the L-DOPA-ropinirole combination resulted in lower peak severity but longer duration of the AIMs compared with L-DOPA alone. At the peak of the AIMs curve (60–120 min), L-DOPA induced a significantly higher total hyperkinesia score, whereas in the end phase (240–270 min), both hyperkinesia and dystonia tended to be more severe after the L-DOPA-ropinirole combination (though reaching statistical significance only for the item, arm dystonia). Our results pave the way for the introduction of a combined L-DOPA-ropinirole challenge test in the early clinical evaluation of antidyskinetic treatments. Furthermore, we propose a machine-learning method to predict CDRS hyperkinesia severity using accelerometer data.
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25.
  • Henz Ryen, Astrid, et al. (författare)
  • Bisabolane sesquiterpenes from the leaves of Lindera benzoin reduce prostaglandin E2 formation in A549 cells
  • 2020
  • Ingår i: Phytochemistry Letters. - : ELSEVIER. - 1874-3900 .- 1876-7486. ; 38, s. 6-11
  • Tidskriftsartikel (refereegranskat)abstract
    • Phytochemical investigation of leaves from the American shrub Lindera benzoin (L.) Blume (Lauraceae) resulted in the isolation of one pure compound 1 and a diastereomeric mixture of 2 and 3. The structures of these new bisabolane sesquiterpenes were elucidated via MS and extensive NMR measurements and identified as 6-(2hydroxy-6-methylhept-5-en-2-yl)-3-(hydroxymethyl)-4-oxocyclohex-2-en-1-yl acetate (1) and 3-(hydroxymethyl)-6-(5-(2-hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl)-4-oxocyclohex-2-en-1-yl acetate (2 and 3). The compounds were evaluated in vitro for their anti-inflammatory activity. In cellular assays, 1-3 reduced pro-inflammatory prostaglandin E2 production in A549 cells in a dose-dependent manner.
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26.
  • Hollfelder, Nina, et al. (författare)
  • The deep population history in Africa
  • 2021
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 30:R1, s. R2-R10
  • Forskningsöversikt (refereegranskat)abstract
    • Africa is the continent with the greatest genetic diversity among humans and the level of diversity is further enhanced by incorporating non-majority groups, which are often understudied. Many of today's minority populations historically practiced foraging lifestyles, which were the only subsistence strategies prior to the rise of agriculture and pastoralism, but only a few groups practicing these strategies remain today. Genomic investigations of Holocene human remains excavated across the African continent show that the genetic landscape was vastly different compared to today's genetic landscape and that many groups that today are population isolate inhabited larger regions in the past. It is becoming clear that there are periods of isolation among groups and geographic areas, but also genetic contact over large distances throughout human history in Africa. Genomic information from minority populations and from prehistoric remains provide an invaluable source of information on the human past, in particular deep human population history, as Holocene large-scale population movements obscure past patterns of population structure. Here we revisit questions on the nature and time of the radiation of early humans in Africa, the extent of gene-flow among human populations as well as introgression from archaic and extinct lineages on the continent.
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27.
  • Jakobsson, Hugo, 1990-, et al. (författare)
  • Pulp-to-palm distance after plate fixation of a distal radius fracture corresponds to functional outcome
  • 2023
  • Ingår i: Archives of physiotherapy. - : BioMed Central (BMC). - 2057-0082. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: Several factors can influence the outcome after a distal radius fracture (DRF). The aim of this study was to assess whether postoperative pulp-to-palm (PTP) distance correlated with functional outcomes after plate fixation of DRF. MATERIALS &METHODS: This is a secondary analysis of a randomized controlled trial aimed to investigate the effects of plate fixation in patients with type-C fractures. Subjects (N = 135) were divided into 2 groups based on PTP distance (equal to or higher than 0 cm) at 4 weeks postoperatively. Outcome measures were collected prospectively at 3, 6 and 12 months and included Patient-Rated Wrist Evaluation (PRWE), Quick Disabilities of the Arm Shoulder and Hand (QuickDASH) scores, wrist range of motion (ROM), Visual Analog Scale (VAS) pain scores, and hand grip strength.RESULTS: Overall, at 3 and 6 months patients with PTP > 0 cm had significantly worse outcomes (PRWE, QuickDASH, wrist ROM) than those with PTP =0 cm. At 12 months, QuickDASH and wrist ROM were still significantly worse. In the volar-plating subgroup, patients with PTP > 0 cm had significantly worse wrist ROM and grip strength at 3 months, but no significant differences were found in subsequent follow-ups. In the combined-plating group, patients with PTP > 0 cm had significantly worse QuickDASH, wrist ROM and grip strength at 3 months. At 6 and 12 months, wrist ROM was still significantly worse.CONCLUSIONS: Measurement of PTP distance appears to be useful to identify patients likely to have worse outcome after plating of a DRF. This could be a tool to improve the allocation of hand rehabilitation resources.
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28.
  • Jakobsson, Per-Johan, et al. (författare)
  • Where traditional Chinese medicine meets Western medicine in the prevention of rheumatoid arthritis
  • 2022
  • Ingår i: Journal of Internal Medicine. - : Wiley-Blackwell. - 0954-6820 .- 1365-2796. ; 292:5, s. 745-763
  • Forskningsöversikt (refereegranskat)abstract
    • Chinese medicine has a long tradition of use against rheumatoid arthritis (RA). The formulations are based on combinations of typically 5-10 plants, which are usually boiled and administered as a decoction or tea. There are few clinical trials performed so the clinical evidence is sparse. One fundamental of traditional medicine is to prevent disease. RA is an autoimmune, inflammatory and chronic disease that primarily affects the joints of 0.5%-1% of the population. In two out of three of the cases, the patients are characterised by the presence of autoantibodies such as the rheumatoid factor and the more disease-specific autoantibody against citrullinated proteins, so-called 'ACPA' (anticitrullinated protein/peptide antibodies). ACPA positivity is also strongly associated with specific variations in the HLA-DRB1 gene, the shared epitope alleles. Together with smoking, these factors account for the major risks of developing RA. In this review, we will summarise the background using certain plant-based formulations based on Chinese traditional medicine for the treatment and prevention of RA and the strategy we have taken to explore the mechanisms of action. We also summarise the major pathophysiological pathways related to RA and how these could be analysed. Finally, we summarise our ideas on how a clinical trial using Chinese herbal medicine to prevent RA could be conducted.
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29.
  • Johansson, Pia A, et al. (författare)
  • A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development
  • 2022
  • Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909 .- 1875-9777. ; 29:1, s. 8-69
  • Tidskriftsartikel (refereegranskat)abstract
    • The human forebrain has expanded in size and complexity compared to chimpanzees despite limited changes in protein-coding genes, suggesting that gene expression regulation is an important driver of brain evolution. Here, we identify a KRAB-ZFP transcription factor, ZNF558, that is expressed in human but not chimpanzee forebrain neural progenitor cells. ZNF558 evolved as a suppressor of LINE-1 transposons but has been co-opted to regulate a single target, the mitophagy gene SPATA18. ZNF558 plays a role in mitochondrial homeostasis, and loss-of-function experiments in cerebral organoids suggests that ZNF558 influences developmental timing during early human brain development. Expression of ZNF558 is controlled by the size of a variable number tandem repeat that is longer in chimpanzees compared to humans, and variable in the human population. Thus, this work provides mechanistic insight into how a cis-acting structural variation establishes a regulatory network that affects human brain evolution.
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30.
  • Kirdok, Emrah, et al. (författare)
  • Metagenomic analysis of Mesolithic chewed pitch reveals poor oral health among stone age individuals
  • 2024
  • Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Prehistoric chewed pitch has proven to be a useful source of ancient DNA, both from humans and their microbiomes. Here we present the metagenomic analysis of three pieces of chewed pitch from Huseby Klev, Sweden, that were dated to 9,890-9,540 before present. The metagenomic profile exposes a Mesolithic oral microbiome that includes opportunistic oral pathogens. We compared the data with healthy and dysbiotic microbiome datasets and we identified increased abundance of periodontitis-associated microbes. In addition, trained machine learning models predicted dysbiosis with 70-80% probability. Moreover, we identified DNA sequences from eukaryotic species such as red fox, hazelnut, red deer and apple. Our results indicate a case of poor oral health during the Scandinavian Mesolithic, and show that pitch pieces have the potential to provide information on material use, diet and oral health.
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31.
  • Kisiel, Marta A., 1984-, et al. (författare)
  • Airspace Dimension Assessment for early detection of lung function impairment in the peripheral airways of firefighters
  • 2023
  • Ingår i: ERJ Open Research. - : European Respiratory Society. - 2312-0541. ; 9:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Firefighters have increased risk of chronic respiratory disease. Standard clinical techniques used in medical checkups may not detect the earliest microstructural changes in peripheral airways. A new technique called Airspace Dimension Assessment (AiDA) has been shown to enable early detection of emphysema in COPD. This method may be useful in the occupational setting to detect early pulmonary changes and enable prevention. The aim of the present study was to evaluate whether AiDA detects changes in the most peripheral airways of firefighters.Methods AiDA, measuring the effective airspace radius (rAiDA) and zero-second recovery (R0), was used as a complement to other standardised lung function measures in 21 male firefighters and 16 age-matched male controls.Results There were significant differences in rAiDA and R0 between firefighters (mean±sd rAiDA 0.301±0.024 mm; mean±sd R0 0.336±0.116 arbitrary units) and controls (mean±sd rAiDA 0.276±0.044 mm; mean±sd R0 0.5760.168 arbitrary units), p=0.03 and p<0.001, respectively. Higher forced vital capacity was found in firefighters (mean 101% of predicted) than in controls (mean 93% of predicted; p=0.03). No significant differences were found with regard to either the ratio between forced expiratory volume in 1 s and forced vital capacity or forced expiratory volume in 1 s. The majority of firefighters had diffusing capacity of the lung for carbon monoxide, oscillometry and single-breath nitrogen washout values within the normal ranges.Conclusion AiDA parameters can provide information on early pulmonary peripheral changes that may not be seen with standard techniques used in screening of pulmonary function.
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32.
  • Larena, Maximilian, et al. (författare)
  • Multiple migrations to the Philippines during the last 50,000 years
  • 2021
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 118:13
  • Tidskriftsartikel (refereegranskat)abstract
    • Island Southeast Asia has recently produced several surprises regarding human history, but the region's complex demography remains poorly understood. Here, we report similar to 2.3 million genotypes from 1,028 individuals representing 115 indigenous Philippine populations and genome-sequence data from two similar to 8,000-y-old individuals from Liangdao in the Taiwan Strait. We show that the Philippine islands were populated by at least five waves of human migration: initially by Northern and Southern Negritos (distantly related to Australian and Papuan groups), followed by Manobo, Sama, Papuan, and Cordilleran-related populations. The ancestors of Cordillerans diverged from indigenous peoples of Taiwan at least similar to 8,000 y ago, prior to the arrival of paddy field rice agriculture in the Philippines similar to 2,500 y ago, where some of their descendants remain to be the least admixed East Asian groups carrying an ancestry shared by all Austronesian-speaking populations. These observations contradict an exclusive "out-of-Taiwan" model of farming-language-people dispersal within the last four millennia for the Philippines and Island Southeast Asia. Sama-related ethnic groups of southwestern Philippines additionally experienced some minimal South Asian gene flow starting similar to 1,000 y ago. Lastly, only a few lowlanders, accounting for <1% of all individuals, presented a low level of West Eurasian admixture, indicating a limited genetic legacy of Spanish colonization in the Philippines. Altogether, our findings reveal a multilayered history of the Philippines, which served as a crucial gateway for the movement of people that ultimately changed the genetic landscape of the Asia-Pacific region.
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33.
  • Liu, Jianyang, et al. (författare)
  • Urinary prostanoids are elevated by anti-TNF and anti-IL6 receptor disease-modifying antirheumatic drugs but are not predictive of response to treatment in early rheumatoid arthritis
  • 2024
  • Ingår i: ARTHRITIS RESEARCH & THERAPY. - 1478-6354 .- 1478-6362. ; 26:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Disease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient's response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy. Methods: This study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-alpha blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B-2 (TXBM), 2,3-dinor-6-keto prostaglandin F-1a (PGIM), leukotriene E-4 (LTE4) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography-mass spectrometry (LC-MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes. Results: Patients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24. Conclusions: Treatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy.
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34.
  • Lundin Gurné, Frida, et al. (författare)
  • Seeking lifestyle counselling at primary health care centres: a cross-sectional study in the Swedish population
  • 2023
  • Ingår i: BMC Primary Care. - : Springer Science and Business Media LLC. - 2731-4553. ; 24:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Millions of people follow an unhealthy lifestyle in terms of tobacco consumption, hazardous use of alcohol, poor eating habits, and insufficient physical activity. Healthy lifestyles can to a large extent prevent and/or delay progression of non-communicable diseases. Factors influencing persons health-seeking behaviour regarding unhealthy lifestyles are of importance for sustainable health-promotive and disease-preventive work in primary health care. Generally, lifestyle interventions within primary health care are seen as feasible, but rarely reach all members of the general population. Few studies have been conducted about the likelihood among the general population to voluntarily contact a primary health care centre for support regarding lifestyle changes. The present study therefore aimed to investigate the general population’s likelihood of contacting a primary health care centre regarding their lifestyles, and factors associated with a lower such likelihood. Methods: A probability sample of adults living in Sweden (n = 3750) were invited to participate in a cross-sectional survey regarding how societal developments affect attitudes and behaviours of the adult Swedish population. Data were collected between September and December 2020. Participants completed a questionnaire about lifestyle changes, and the data were analysed using descriptive statistics, Chi-square test and logistic regression analysis. Results: The response rate was 52.0% (n = 1 896). Few persons responded that they would be likely to contact a primary health care centre for support regarding their lifestyles. Factors predicting a lower likelihood of contacting primary health care included few yearly visits to a primary health care centre, male sex, and living in a rural area. Conclusions: Primary health care centres are not the first choice for lifestyle counselling for the majority of adults living in Sweden. We have identified factors predicting low likelihood of using the support available at these centres. In order to work with sustainable and visible health-promotive and disease-preventive strategies at primary health care centres, these settings need to find valid methods to involve and collaborate with the members of the general community, to meet the needs of a population struggling with unhealthy lifestyles.
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35.
  • Mattila, Tiina M., et al. (författare)
  • Genetic continuity, isolation, and gene flow in Stone Age Central and Eastern Europe
  • 2023
  • Ingår i: Communications Biology. - : Springer Nature. - 2399-3642. ; 6:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The genomic landscape of Stone Age Europe was shaped by multiple migratory waves and population replacements, but different regions do not all show similar patterns. To refine our understanding of the population dynamics before and after the dawn of the Neolithic, we generated and analyzed genomic sequence data from human remains of 56 individuals from the Mesolithic, Neolithic, and Eneolithic across Central and Eastern Europe. We found that Mesolithic European populations formed a geographically widespread isolation-by-distance zone ranging from Central Europe to Siberia, which was already established 10,000 years ago. We found contrasting patterns of population continuity during the Neolithic transition: people around the lower Dnipro Valley region, Ukraine, showed continuity over 4000 years, from the Mesolithic to the end of the Neolithic, in contrast to almost all other parts of Europe where population turnover drove this cultural change, including vast areas of Central Europe and around the Danube River. Genome-wide sequencing of 56 ancient hunter-gatherer and early farmer individuals from Stone Age Central and Eastern Europe reveals striking population continuity in the east in contrast to central Europe that displays extensive admixture.
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36.
  • McKenna, James, 1987-, et al. (författare)
  • Detecting population continuity and ghost admixture among ancient genomes
  • 2022
  • Ingår i: biorxiv. - 2692-8205.
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Ancient DNA (aDNA) can prove a valuable resource when investigating theevolutionary relationships between ancient and modern populations. Per-forming demographic inference using datasets that include aDNA sampleshowever, requires statistical methods that explicitly account for the differ-ences in drift expected among a temporally distributed sample. Such driftdue to temporal structure can be challenging to discriminate from admix-ture from an unsampled, or “ghost”, population, which can give rise to verysimilar summary statistics and confound methods commonly used in pop-ulation genetics. Sequence data from ancient individuals also have uniquecharacteristics, including short fragments, increased sequencing-error rates,and often limited genome-coverage that poses further challenges. Here wepresent a novel and conceptually simple approach for assessing questionsof population continuity among a temporally distributed sample. We notethat conditional on heterozygote sites in an individual genome at a particu-lar point in time, the mean proportion of derived variants at those sites inother individuals has different expectations forwards in time and backwardsin time. The difference in these processes enables us to construct a statis-tic that can detect population continuity in a temporal sample of genomes.We can show that the statistic is sensitive to historical admixture eventsfrom un-sampled populations. Simulations are used to evaluate the power ofthis approach. We investigate a set of ancient genomes from Early NeolithicScandinavia to assess levels of population continuity to an earlier Mesolithicindividual. Individuals from hunter-gathering Neolithic Pitted Ware cultureshow marked continuity with the Mesolithic individual, whereas the contem-porary Neolithic individuals from the and farming Funnel Beaker culturedisplay much less continuity.
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37.
  • McKenna, James, 1987- (författare)
  • Divergence, admixture and continuity in the human past : Demographic inference using ancient and modern genomes
  • 2022
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Demographic forces shaping the genetic variation we observe today can include population divergences, admixture events and continuity through time. The advancement of high-throughput sequencing technologies, together with developments in molecular and bio-informatics methods, mean the number of ancient genomes available for inference has risen steeply. To make effective use of aDNA however, inference tools need to be developed that account for temporal as well as geographic sampling of genomes. Here I have developed, evaluated and applied methods for estimating divergence times between ancient and modern populations. I used simulation to study the sensitivity of these approaches to violations of model assumptions, before applying them to study the history of population divergence between pairs of populations from a global panel. Non-tree-like demography is common in the human past, with evidence of ancestral structure in the form of archaic admixture in the genomes of all non-African modern humans. Using SNP-array data collected from 118 ethnic groups in the Philippines, I show that the highest levels of Denisovan ancestry are found among the Ayta Magbukon, further highlighting the complex history between modern human groups and the archaic hominins occupying Eurasia before our arrival. Among the most important contributions population genetics has made to the study of the human past is the demonstration that cultural transitions and spread of technologies were often associated with migrating groups of people. This can result in the admixture, displacement or replacement of populations, and aDNA provides us with the opportunity to assess these trends directly through time. I developed a statistical tool to detect population continuity through time, evaluating its performance using simulation. Applied to a dataset of ancient genomes from Early Neolithic Scandinavia, I demonstrate population continuity in the hunter-gathering Pitted Ware culture, despite these people overlapping both geographically and temporally with farmers of the Funnel Beaker culture. In another study of the hunter-gatherer ancestors of the San people of southern Africa, I show evidence that this group exhibited long-term population isolation, remaining unaffected by admixture from outside southern Africa until surprisingly recent times. Using these ancient genomes, I provide further evidence that all modern Khoe-San populations exhibit significant levels of admixture with people of non-Khoe-San ancestry, demonstrating the strong impact migrations in this region have had in the past ~2,000 years.
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38.
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39.
  • Möller, Per, et al. (författare)
  • Deglaciation history and subsequent lake dynamics in the Siljan region, south-central Sweden, based on new LiDAR evidence and sediment records
  • 2022
  • Ingår i: Earth Surface Processes and Landforms. - : Wiley. - 0197-9337 .- 1096-9837. ; 47, s. 3515-3545
  • Tidskriftsartikel (refereegranskat)abstract
    • The Siljan region hosts Europe´s largest impact structure. The high-relief landscape, with a central granite dome bordered by lake basins, contains an array of glacial and shore-level landforms. We investigated its deglaciation history by mapping and analysing landforms on high resolution LiDAR-based Digital Surface Models coupled with well-dated sediment successions from peat and lake sediment cores. The granite dome and bordering areas are characterized by streamlined terrain and ribbed moraine with a streamlined overprint. These suggest an ice-flow direction from NNW with wet-based thermal conditions prior to deglaciation. During its retreat, the ice sheet was split into thinner plateau ice and thicker basin ice. Sets of low-gradient glaciofluvial erosion channels suggest intense ice-lateral meltwater drainage across gradually ice-freed slopes, while 'down-the-slope' erosion channels and eskers show meltwater drainage from stagnated plateau ice. Thick basin ice receded with a subaqueous margin across the deep Siljan–Orsasjön Basin c. 10,700–10,500 cal. BP. During ice recession the ingression of the Baltic Ancylus Lake led to diachronous formation of highest shoreline marks, from c. 207 m in the south to c. 220 m a.s.l. in the north. Differential uplift resulted in shallowing of the water body, which led to the isolation of the Siljan–Orsasjön Basin from the Baltic Basin at c. 9800 cal. BP. The post-isolation water body – the ‘Ancient Lake Siljan' – was drained through the ancient Åkerö Channel with a water level at 168–169 m a.s.l. during c. 1000 years. A later rerouting of the outlet to the present course was initiated at c. 8800 cal. BP, which led to a lake-level lowering of 6–7 m to today’s level of Lake Siljan (c. 162 m a.s.l.). This study shows the strength of an integrated methodological approach for deciphering the evolution of a complex landscape, combining highly resolved geomorphological analysis with well-dated sediment successions.
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40.
  • Möller, Per, et al. (författare)
  • Deglaciation history and subsequent lake dynamics in the Siljan region, south-central Sweden - LiDAR evidence and sediment records
  • 2024
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • The Siljan region hosts Europe´s largest impact structure. The high-relief landscape, with a central granite dome bordered by lake basins, contains an array of glacial and shore-level landforms. We investigated its deglaciation history by mapping and analysing landforms on high resolution LiDAR-based Digital Surface Models coupled with well-dated sediment successions from peat and lake sediment cores. The granite dome and bordering areas are characterized by streamlined terrain and ribbed moraine with a streamlined overprint. These suggest an ice-flow direction from NNW with wet-based thermal conditions prior to deglaciation. During its retreat, the ice sheet was split into thinner plateau ice and thicker basin ice. Sets of low-gradient glaciofluvial erosion channels suggest intense ice-lateral meltwater drainage across gradually ice-freed slopes, while 'down-the-slope' erosion channels and eskers show meltwater drainage from stagnated plateau ice. Thick basin ice receded with a subaqueous margin across the deep Siljan–Orsasjön Basin c. 10,700–10,500 cal. BP. During ice recession the ingression of the Baltic Ancylus Lake led to diachronous formation of highest shoreline marks, from 207 m in the south to 220 m a.s.l. in the north. Differential uplift resulted in shallowing of the water body, which led to the isolation of the Siljan¬–Orsasjön Basin from the Baltic Basin at c. 9800 cal. BP. The post-isolation water body – the ‘Ancient Lake Siljan' – was drained through the ancient Åkerö Channel with a water level at 168–169 m a.s.l. during c. 1000 years. A later rerouting of the outlet to the present course was initiated at c. 8800 cal. BP, which led to a lake-level lowering of 6–7 m to today’s level of Lake Siljan (162 m a.s.l.). This study shows the strength of an integrated methodological approach for deciphering the evolution of a complex landscape, combining highly resolved geomorphological analysis with well-dated sediment successions.
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41.
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42.
  • Notarnicola, Antonella, et al. (författare)
  • Longitudinal assessment of reactivity and affinity profile of anti-Jo1 autoantibodies to distinct HisRS domains and a splice variant in a cohort of patients with myositis and anti-synthetase syndrome
  • 2022
  • Ingår i: Arthritis Research & Therapy. - : Springer Nature. - 1478-6362. ; 24:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background To address the reactivity and affinity against histidyl-transfer RNA synthetase (HisRS) autoantigen of anti-Jo1 autoantibodies from serum and bronchoalveolar lavage fluid (BALF) in patients with idiopathic inflammatory myopathies/anti-synthetase syndrome (IIM/ASSD). To investigate the associations between the reactivity profile and clinical data over time. Methods Samples and clinical data were obtained from (i) 25 anti-Jo1(+) patients (19 sera with 16 longitudinal samples and 6 BALF/matching sera at diagnosis), (ii) 29 anti-Jo1(-) patients (25 sera and 4 BALF/matching sera at diagnosis), and (iii) 27 age/gender-matched healthy controls (24 sera and 3 BALF/matching sera). Reactivity towards HisRS full-length (HisRS-FL), three HisRS domains (WHEP, antigen binding domain (ABD), and catalytic domain (CD)), and the HisRS splice variant (SV) was tested. Anti-Jo1 IgG reactivity was evaluated by ELISA and western blot using IgG purified from serum by affinity chromatography. In paired serum-BALF, anti-Jo1 IgG and IgA reactivity was analyzed by ELISA. Autoantibody affinity was measured by surface plasmon resonance using IgG purified from sera. Correlations between autoantibody reactivity and clinical data were evaluated at diagnosis and longitudinally. Results Anti-Jo1 IgG from serum and BALF bound HisRS-FL, WHEP, and SV with high reactivity at the time of diagnosis and recognized both conformation-dependent and conformation-independent HisRS epitopes. Anti-HisRS-FL IgG displayed high affinity early in the disease. At the time of IIM/ASSD diagnosis, the highest autoantibody levels against HisRS-FL were found in patients ever developing interstitial lung disease (ILD) and arthritis, but with less skin involvement. Moreover, the reactivity of anti-WHEP IgG in BALF correlated with poor pulmonary function. Levels of autoantibodies against HisRS-FL, HisRS domains, and HisRS splice variant generally decreased over time. With some exceptions, longitudinal anti-HisRS-FL antibody levels changed in line with ILD activity. Conclusion High levels and high-affinity anti-Jo1 autoantibodies towards HisRS-FL were found early in disease in sera and BALF. In combination with the correlation of anti-HisRS-FL antibody levels with ILD and ILD activity in longitudinal samples as well as of anti-WHEP IgG in BALF with poor pulmonary function, this supports the previously raised hypothesis that the lung might have a role in the immune reaction in anti-Jo1-positive patients.
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43.
  • Pertsinidou, Eleftheria, et al. (författare)
  • In early rheumatoid arthritis, anticitrullinated peptide antibodies associate with low number of affected joints and rheumatoid factor associates with systemic inflammation
  • 2024
  • Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 83:3, s. 277-287
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: To investigate how individual rheumatoid arthritis (RA) autoantibodies associate with individual signs and symptoms at the time of RA diagnosis.Methods: IgA, IgG, IgM rheumatoid factor (RF), antibodies against cyclic citrullinated peptide version 2 (anti-CCP2) and 16 individual antibodies against citrullinated protein (ACPA) reactivities were analysed centrally in baseline sera from 1600 patients with RA classified according to the 1987 American College of Rheumatology (ACR) criteria. These results were related to C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), number of swollen and tender joints (SJC and TJC), 28-joint disease activity scores (DAS28 and DAS28CRP), global disease activity evaluated by the patients and Health Assessment Questionnaire, all obtained at baseline.Results: Individually, all autoantibodies except immunoglobulin G (IgG) RF associated with low SJC and TJC and with high ESR. In IgM RF-negative patients, ACPA associated strictly with low number of swollen and tender joints. This association persisted in multiple regression and stratified analyses where IgM and IgA RF instead associated with inflammation expressed as ESR. Among subjects without any ACPA peptide reactivity, there was no association between RF isotypes and ESR. The effect of RF on ESR increased with the number of ACPA reactivities, especially for IgM RF. In patients fulfilling the 1987 ACR criteria without taking RF into account, associations between IgM RF and high ESR, as well as between ACPA and low joint counts, remained.Conclusion: Whereas ACPA associate with low counts of affected joints in early RA, RF associates with elevated measures of systemic inflammation in an ACPA-dependent manner. This latter finding corroborates in vitro models of ACPA and RF in immune complex-induced inflammation. These phenotypic associations are independent of classification criteria.
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44.
  • Petersson-Sjögren, Madeleine, et al. (författare)
  • Airspace Dimension Assessment with Nanoparticles (AiDA) in Comparison to Established Pulmonary Function Tests
  • 2022
  • Ingår i: International Journal of Nanomedicine. - : Dove Medical Press Ltd. - 1176-9114 .- 1178-2013. ; 17, s. 2777-2790
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Airspace Dimensions Assessment with nanoparticles (AiDA) is a new method for non-invasive measurement of pulmonary distal airspaces. The aim of this study was to compare AiDA measurements with other pulmonary function variables to better understand the potential of AiDA in a clinical context. Methods: AiDA measurements and pulmonary function tests were performed in 695 subjects as part of the Swedish CArdioPulmonary bioImage Study. The measurement protocol included spirometry, measurement of diffusing capacity of carbon monoxide, oscillometry and pulmonary computed tomography. AiDA indices were compared to all other pulmonary examination measurements using multivariate statistical analysis. Results: Our results show that AiDA measurements were significantly correlated with other pulmonary function examination indices, although covariance was low. We found that AiDA variables explained variance in the data that other lung function variables only influenced to a minor extent. Conclusion: We conclude that the AiDA method provides information about the lung that is inaccessible with more conventional lung function techniques. © 2022 Petersson-Sjögren et al.
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45.
  • Plue, Jan, et al. (författare)
  • Buffering effects of soil seed banks on plant community composition in response to land use and climate
  • 2020
  • Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 30:1, s. 128-139
  • Tidskriftsartikel (refereegranskat)abstract
    • AimClimate and land use are key determinants of biodiversity, with past and ongoing changes posing serious threats to global ecosystems. Unlike most other organism groups, plant species can possess dormant life‐history stages such as soil seed banks, which may help plant communities to resist or at least postpone the detrimental impact of global changes. This study investigates the potential for soil seed banks to achieve this.Location Europe.Time period 1978–2014.Major taxa studied Flowering plantsMethodsUsing a space‐for‐time/warming approach, we study plant species richness and composition in the herb layer and the soil seed bank in 2,796 community plots from 54 datasets in managed grasslands, forests and intermediate, successional habitats across a climate gradient.ResultsSoil seed banks held more species than the herb layer, being compositionally similar across habitats. Species richness was lower in forests and successional habitats compared to grasslands, with annual temperature range more important than mean annual temperature for determining richness. Climate and land‐use effects were generally less pronounced when plant community richness included seed bank species richness, while there was no clear effect of land use and climate on compositional similarity between the seed bank and the herb layer.Main conclusionsHigh seed bank diversity and compositional similarity between the herb layer and seed bank plant communities may provide a potentially important functional buffer against the impact of ongoing environmental changes on plant communities. This capacity could, however, be threatened by climate warming. Dormant life‐history stages can therefore be important sources of diversity in changing environments, potentially underpinning already observed time‐lags in plant community responses to global change. However, as soil seed banks themselves appear, albeit less, vulnerable to the same changes, their potential to buffer change can only be temporary, and major community shifts may still be expected.
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46.
  • Plue, Jan, et al. (författare)
  • European soil seed bank communities across a climate and land-cover gradient
  • 2020
  • Annan publikationabstract
    • This is the data set used for the publication Buffering effects of soil seed banks on plant community composition in response to land use and climate, published in the journal Global Ecology and Biogeography.Aim.Climate and land use are key determinants of biodiversity, with past and ongoing changes posing serious threats to global ecosystems. Unlike most other organism groups, plant species can possess dormant life-history stages such as soil seed banks, which may help plant communities to resist or at least postpone the detrimental impact of global changes. This study investigates the potential for soil seed banks to achieve this.Location. EuropeTime period. 1978 – 2014Major taxa studied. Flowering plantsMethods.Using a space-for-time/warming approach, we study plant species richness and composition in the herb layer and the soil seed bank in 2796 community plots from 54 datasets in managed grasslands, forests and intermediate, successional habitats across a climate gradient.Results.Soil seed banks held more species than the herb layer, being compositionally similar across habitats. Species richness was lower in forests and successional habitats compared to grasslands, with annual temperature range more important than mean annual temperature for determining richness. Climate and land use effects were generally less pronounced when plant community richness included seed bank species richness, while there was no clear effect of land use and climate on compositional similarity between the seed bank and the herb layer.Main conclusions.High seed bank diversity and compositional similarity between the herb layer and seed bank plant communities may provide a potentially important functional buffer against the impact of ongoing environmental changes on plant communities. This capacity could, however, be threatened by climate warming. Dormant life-history stages can therefore be important sources of diversity in changing environments, potentially underpinning already observed time-lags in plant community responses to global change. However, as soil seed banks themselves appear, albeit less, vulnerable to the same changes, their potential to buffer change can only be temporary, and major community shifts may still be expected.MethodsThis dataset is a collection of 41 published and 5 unpublished data sets, consisting of 2796 plots with corresponding seed bank and herb layer community data. Sampling effort varied across data sets, but involved sampling of the soil and subsequent germination trials in a greenhouse to determine seed bank composition. Herb layer communities were determined by the identification of plants in relevés. Please consult the readme file and published paper for further details.Usage NotesPlease contact database or individual data set authors for further information and collaboration when using the data set or any of its component parts. Please also note that some of these data sets have already been published alongside their orginal papers. Finally, please cite data and datasets according to community standards.
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47.
  • Preger, Charlotta, et al. (författare)
  • Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies
  • 2023
  • Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 134
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Autoantibodies are thought to play a key role in the pathogenesis of idiopathic inflammatory my-opathies (IIM). However, up to 40% of IIM patients, even those with clinical manifestations of anti-synthetase syndrome (ASSD), test seronegative to known myositis-specific autoantibodies. We hypothesized the existence of new potential autoantigens among human cytoplasmic aminoacyl tRNA synthetases (aaRS) in patients with IIM.Methods: Plasma samples from 217 patients with IIM according to 2017 EULAR/ACR criteria, including 50 pa-tients with ASSD, 165 without, and two with unknown ASSD status were identified retrospectively, as well as age and gender-matched sera from 156 population controls, and 219 disease controls. Patients with previously documented ASSD had to test positive for at least one of the five most common anti-aaRS autoantibodies (anti-Jo1,-PL7,-PL12,-EJ, and-OJ) and present with one or more of the following clinical manifestations: interstitial lung disease, myositis, arthritis, Raynaud's phenomenon, fever, or mechanic's hands. Demographics, laboratory, and clinical data of the IIM cohort (ASSD and non-ASSD) were compared. Samples were screened using a multiplex bead array assay for presence of autoantibodies against a panel of 117 recombinant protein variants, representing 33 myositis-related proteins, including all nineteen cytoplasmic aaRS. Prospectively collected clinical data for the IIM cohort were retrieved and compared between groups within the IIM cohort and correlated with the results of the autoantibody screening. Principal component analysis was used to analyze clinical manifestations between ASSD, non-ASSD groups, and individuals with novel anti-aaRS autoantibodies. Results: We identified reactivity towards 16 aaRS in 72 of the 217 IIM patients. Twelve patients displayed reactivity against nine novel aaRS. The novel autoantibody specificities were detected in four previously sero-negative patients for myositis-specific autoantibodies and eight with previously detected myositis-specific au-toantibodies. IIM individuals with novel anti-aaRS autoantibodies (n = 12) all had signs of myositis, and they had either muscle weakness and/or muscle enzyme elevation, 2/12 had mechanic's hands, 3/12 had interstitial lung disease, and 2/12 had arthritis. The individuals with novel anti-aaRS and a pathological muscle biopsy all presented widespread up-regulation of major histocompatibility complex class I. The reactivities against novel aaRS could be confirmed in ELISA and western blot. Using the multiplex bead array assay, we could confirm previously known reactivities to four of the most common aaRS (Jo1, PL12, PL7, and EJ (n = 45)) and identified patients positive for anti-Zo,-KS, and-HA (n = 10) that were not previously tested. A low frequency of anti-aaRS autoantibodies was also detected in controls.Conclusion: Our results suggest that most, if not all, cytoplasmic aaRS may become autoantigenic. Autoantibodies against new aaRS may be found in plasma of patients previously classified as seronegative with potential high clinical relevance.
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48.
  • Reed, Evan, et al. (författare)
  • Presence of autoantibodies in "seronegative" rheumatoid arthritis associates with classical risk factors and high disease activity
  • 2020
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 22:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundRheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays. Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA. Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative.MethodsAnti-CCP2 IgG, 19 ACPA fine-specificities, IgM/IgG/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls. Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5 years were investigated for different antibody-defined RA subsets.ResultsAutoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies. HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence. Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA. Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined “seronegative” RA, associated with worse clinical outcome.Conclusions“Seronegative” RA is not truly a seronegative disease subset. Additional screening for ACPA fine-specificities and IgA/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2−/IgM RF− patients with a high need for active treatment.
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49.
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50.
  • Roos Ljungberg, Karin, 1988- (författare)
  • Secretory Autoantibodies in Rheumatoid Arthritis
  • 2022
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease in which autoantibodies, such as anti-citrullinated protein antibodies (ACPA), can be detected in the serum of patients. Autoantibodies may appear in the circulation years before clinical signs of joint inflammation occur, indicating that early immunological pathogenetic steps take place outside of the joints. Although many of these mechanisms are currently unknown, the initial events leading up to ACPA production are thought to occur at mucosal surfaces. In this thesis, mucosa-associated secretory ACPA are investigated in the circulation and in local mucosal secretions to: (i) improve the understanding of the mucosal connection in RA; and (ii) investigate whether these antibodies can improve diagnostics and prognostics in early RA. We identified circulating secretory component containing (SC) ACPA in a subpopulation of patients (both early and established RA) and at-risk patients, with a prevalence of 16%-21%. In addition, SC ACPA was detected in bronchoalveolar lavage fluid (BALF) and IgA ACPA in saliva, indicating local production in the lungs and in the oral cavity. In at-risk patients who were positive for IgG ACPA, we found that the levels of circulating SC ACPA at inclusion predicted arthritis development. Circulating SC ACPA was associated with higher disease activity, including increased levels of inflammatory markers, in patients with early RA. Levels of circulating SC ACPA were associated with high-resolution computed tomography (HRCT) findings (parenchymal lung abnormalities and bronchiectasis) and smoking, but not with risk genes (shared epitope). We confirmed the presence of salivary ACPA and identified a novel association with increased disease activity and functional disability. In summary, SC ACPA is present in the sera of patients with RA who manifest different phases of the disease, and we found associations with arthritis onset, smoking, systemic inflammation, and lung abnormalities. SC ACPA is also detectable in mucosal secretions from the lungs and the oral cavity. These findings suggest that mucosal ACPA production may be an important factor in RA development and progression, and that serum SC ACPA should be further evaluated as a prognostic marker for disease onset among at-risk individuals. 
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