| 1. |
- Adolfsson, Annsofie, 1960-, et al.
(author)
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Miscarriage : Evidence Based Information for the Web and Its Development Procedure
- 2015
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In: Advances in Sexual Medicine. - Irvine, USA : Scientific Research Publishing. - 2164-5191 .- 2164-5205. ; 5:4, s. 89-110
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Journal article (peer-reviewed)abstract
- Objective: The aim of this paper is to describe the process of developing web information on miscarriage based on scientific evidence, for women and couples in Sweden experiencing miscarriage. Method: A participatory design was used which included researchers, professional xperts and users. A participatory design was used involving researchers, professional experts and users. The information was developed in six stages: 1) identifying the needs of information; 2) identifying and constructing the main areas of information and its paths; 3) identifying and inviting experts for revision; 4) developing the text; 5) reviewing the text; 6) design and structuring for adaption to website. Results: The text of information developed gradually based on the seven steps. The final text comprised three parts: 1) what is miscarriage; 2) experiences of miscarriage; 3) processing and lanning for new pregnancy. Conclusion: Using participatory design was time and resource consuming, however it was functional for producing appropriate information for the target group. The developed evidence based facts text is assumed to be a complement to the information that is provided by the health care system.
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| 2. |
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| 3. |
- Berglund, Emelie, et al.
(author)
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Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity
- 2018
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- Intra-tumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor microenvironment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies.
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| 4. |
- Erickson, A, et al.
(author)
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Spatially resolved clonal copy number alterations in benign and malignant tissue
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 608:7922, s. 360-
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Journal article (peer-reviewed)abstract
- Defining the transition from benign to malignant tissue is fundamental to improving early diagnosis of cancer1. Here we use a systematic approach to study spatial genome integrity in situ and describe previously unidentified clonal relationships. We used spatially resolved transcriptomics2 to infer spatial copy number variations in >120,000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue using an organ-wide approach focused on the prostate. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of capturing the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy.
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| 5. |
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| 6. |
- Erickson, Andrew, et al.
(author)
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The spatial landscape of clonal somatic mutations in benign and malignant tissue
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Other publication (other academic/artistic)abstract
- Defining the transition from benign to malignant tissue is fundamental to improve early diagnosis of cancer. Here, we provide an unsupervised approach to study spatial genome integrity in situ to gain molecular insight into clonal relationships. We employed spatially resolved transcriptomics to infer spatial copy number variations in >120 000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of an unsupervised approach to capture the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy.
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| 7. |
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| 8. |
- Herrmann, Inga, 1978-, et al.
(author)
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Markbaserad rening - design, funktion och bedömningkriterier vid tillsyn
- 2021
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Reports (other academic/artistic)abstract
- Markbaserade reningsanläggningar för avloppsvatten har använts länge i Sverige och anses som en robust och driftsäker reningsmetod. Kommunerna som ansvarar för tillsynen har vid inspektionsbesök av anläggningar observerat olika brister i sådana markbaserade anläggningar, t.ex. förhöjd slamförekomst i slamavskiljare, fördelningsbrunn, spridarledningar och/eller luftningsrör, för höga vattennivåer i delar av anläggningen och/eller problem med ventilation. Dessa problem har också uppmärksammats i olika projekt. Det är dock generellt svårt att bedöma huruvida dessa brister har en negativ påverkan på reningsanläggningens funktion. Det finns ett behov av ökad kunskap om när en markbaserad anläggning fungerar eller inte och hur detta ska bedömas, både för att en anläggning inte ska dömas ut i onödan och för att en anläggning som inte fungerar tillfredsställande får rätt typ av åtgärd.I detta projekt undersöktes design-, funktions- och tillsynsprinciper för markbaserade anläggningar med hjälp av litteraturstudier och intervjuer. Syftet var att bidra till utformning av relevanta bedömningskriterier för markbaserade reningsanläggningar som kan användas vid prövning och tillsyn. Målen var att:- granska litteraturen inom markbaserad rening för att lista viktiga faktorer som påverkar funktionen,- jämföra svenska dimensioneringskriterier för slamavskiljare och infiltrationer med kriterier som används i andra länder (Norge och USA),- beskriva hur tillsyn av markbaserade anläggningar genomförs hos kommuner som är aktiva inom tillsyn,- belysa hur olika kommuner resonerar angående bedömningen av olika typer av brister (i detta mål ingår att bedöma hur allvarliga olika typer av brister är – det vill säga om bristerna kräver en uppföljning i form av föreläggande eller förbud eller om det räcker med information eller enklare uppföljning – och hur pass stor samstämmighet som finns mellan olika kommuner vid bedömning av bristers allvarlighet),- uppmärksamma svårigheter med att bedöma funktionen i markbaserade anläggningar och peka ut framtida områden som behöver vidare arbete, samt att- sammanfatta hur tillsyn bedrivs i andra länder och resonera kring vilka lärdomar som kan dras därur.
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| 9. |
- Lundgren, Anna, 1974, et al.
(author)
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Plasmablasts in previously immunologically naive COVID-19 patients express markers indicating mucosal homing and secrete antibodies cross-reacting with SARS-CoV-2 variants and other beta-coronaviruses
- 2023
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In: Clinical and Experimental Immunology. - 0009-9104 .- 1365-2249. ; 213:2, s. 173-89
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Journal article (peer-reviewed)abstract
- Antigen-specific class-switched antibodies are detected at the same time or even before IgM in serum of non-vaccinated individuals infected with SARS-CoV-2. These derive from the first wave of plasmablasts formed. Hence, the phenotype and specificity of plasmablasts can reveal information about early B-cell activation. Here we have analyzed B cells and plasmablasts circulating in blood of COVID-19 patients not previously exposed to SARS-CoV-2 during and after disease. We find that during infection with the original Wuhan strain, plasmablasts in blood produce IgA1, IgG1, and IgM, and that most express CCR10 and integrin beta 1, only some integrin beta 7, while the majority lack CCR9. Plasmablast-secreted antibodies are reactive to the spike (S) and nucleocapsid (N) proteins of the Wuhan strain as well as later variants of concern, but also bind S proteins from endemic and non-circulating betacoronaviruses. In contrast, after recovery, antibodies produced from memory B cells target variants of SARS-CoV-2 and SARS-CoV-1 but compared to previously non-infected individuals do not show increased binding to endemic coronaviruses. This suggests that the early antibody response to a large extent stems from pre-existing cross-reactive class-switched memory B cells, and that although newly formed memory cells target the novel SARS-CoV-2 virus the numbers of broadly cross-reactive memory B cells do not increase extensively. The observations give insight into the role of pre-existing memory B cells in early antibody responses to novel pathogens and may explain why class-switched antibodies are detected early in the serum of COVID-19 patients. During an infection, plasmablasts circulating in blood represent ongoing formation of antibody-producing cells from activated B cells. Here we study the early plasmablasts in previously naive COVID-19 patients arriving at hospital. We find extensive cross-reactivity to circulating and non-circulating beta-coronaviruses, that IgA1 responses dominate, and that the cells express markers suggesting mucosal homing.
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| 10. |
- Marklund, Emelie, et al.
(author)
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Longitudinal Follow Up of Immune Responses to SARS-CoV-2 in Health Care Workers in Sweden With Several Different Commercial IgG-Assays, Measurement of Neutralizing Antibodies and CD4+ T-Cell Responses.
- 2021
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In: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Journal article (peer-reviewed)abstract
- The risk of SARS-CoV-2 infection among health care workers (HCWs) is a concern, but studies that conclusively determine whether HCWs are over-represented remain limited. Furthermore, methods used to confirm past infection vary and the immunological response after mild COVID-19 is still not well defined.314 HCWs were recruited from a Swedish Infectious Diseases clinic caring for COVID-19 patients. IgG antibodies were measured using two commercial assays (Abbot Architect nucleocapsid (N)-assay and YHLO iFlash-1800 N and spike (S)-assays) at five time-points, from March 2020 to January 2021, covering two pandemic waves. Seroprevalence was assessed in matched blood donors at three time-points. More extensive analyses were performed in 190 HCWs in September/October 2020, including two additional IgG-assays (DiaSorin LiaisonXL S1/S2 and Abbot Architect receptor-binding domain (RBD)-assays), neutralizing antibodies (NAbs), and CD4+ T-cell reactivity using an in-house developed in vitro whole-blood assay based on flow cytometric detection of activated cells after stimulation with Spike S1-subunit or Spike, Membrane and Nucleocapsid (SMN) overlapping peptide pools.Seroprevalence was higher among HCWs compared to sex and age-matched blood donors at all time-points. Seropositivity increased from 6.4% to 16.3% among HCWs between May 2020 and January 2021, compared to 3.6% to 11.9% among blood donors. We found significant correlations and high levels of agreement between NAbs and all four commercial IgG-assays. At 200-300 days post PCR-verified infection, there was a wide variation in sensitivity between the commercial IgG-assays, ranging from <30% in the N-assay to >90% in the RBD-assay. There was only moderate agreement between NAbs and CD4+ T-cell reactivity to S1 or SMN. Pre-existing CD4+ T-cell reactivity was present in similar proportions among HCW who subsequently became infected and those that did not.HCWs in COVID-19 patient care in Sweden have been infected with SARS-CoV-2 at a higher rate compared to blood donors. We demonstrate substantial variation between different IgG-assays and propose that multiple serological targets should be used to verify past infection. Our data suggest that CD4+ T-cell reactivity is not a suitable measure of past infection and does not reliably indicate protection from infection in naive individuals.
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| 11. |
- Marklund, Emelie, et al.
(author)
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Serum-IgG responses to SARS-CoV-2 after mild and severe COVID-19 infection and analysis of IgG non-responders.
- 2020
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 15:10
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Journal article (peer-reviewed)abstract
- To accurately interpret COVID-19 seroprevalence surveys, knowledge of serum-IgG responses to SARS-CoV-2 with a better understanding of patients who do not seroconvert, is imperative. This study aimed to describe serum-IgG responses to SARS-CoV-2 in a cohort of patients with both severe and mild COVID-19, including extended studies of patients who remained seronegative more than 90 days post symptom onset.SARS-CoV-2-specific IgG antibody levels were quantified using two clinically validated and widely used commercial serological assays (Architect, Abbott Laboratories and iFlash 1800, YHLO), detecting antibodies against the spike and nucleocapsid proteins.Forty-seven patients (mean age 49 years, 38% female) were included. All (15/15) patients with severe symptoms and 29/32 (90.6%) patients with mild symptoms of COVID-19 developed SARS-CoV-2-specific IgG antibodies in serum. Time to seroconversion was significantly shorter (median 11 vs. 22 days, P = 0.04) in patients with severe compared to mild symptoms. Of the three patients without detectable IgG-responses after >90 days, all had detectable virus-neutralizing antibodies and in two, spike-protein receptor binding domain-specific IgG was detected with an in-house assay. Antibody titers were preserved during follow-up and all patients who seroconverted, irrespective of the severity of symptoms, still had detectable IgG levels >75 days post symptom onset.Patients with severe COVID-19 both seroconvert earlier and develop higher concentrations of SARS-CoV-2-specific IgG than patients with mild symptoms. Of those patients who not develop detectable IgG antibodies, all have detectable virus-neutralizing antibodies, suggesting immunity. Our results showing that not all COVID-19 patients develop detectable IgG using two validated commercial clinical methods, even over time, are vital for the interpretation of COVID-19 seroprevalence surveys.
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| 12. |
- Marklund, Maja, et al.
(author)
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Spatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones
- 2022
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- The molecular mechanisms underlying lethal castration-resistant prostate cancer remain poorly understood, with intratumoral heterogeneity a likely contributing factor. To examine the temporal aspects of resistance, we analyze tumor heterogeneity in needle biopsies collected before and after treatment with androgen deprivation therapy. By doing so, we are able to couple clinical responsiveness and morphological information such as Gleason score to transcriptome-wide data. Our data-driven analysis of transcriptomes identifies several distinct intratumoral cell populations, characterized by their unique gene expression profiles. Certain cell populations present before treatment exhibit gene expression profiles that match those of resistant tumor cell clusters, present after treatment. We confirm that these clusters are resistant by the localization of active androgen receptors to the nuclei in cancer cells post-treatment. Our data also demonstrates that most stromal cells adjacent to resistant clusters do not express the androgen receptor, and we identify differentially expressed genes for these cells. Altogether, this study shows the potential to increase the power in predicting resistant tumors. Spatial heterogeneity in prostate cancer can contribute to its resistance to androgen deprivation therapy (ADT). Here, the authors analyse prostate cancer samples before and after ADT using Spatial Transcriptomics, and find heterogeneous pre-treatment tumour cell populations and stromal cells that are associated with resistance.
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| 13. |
- Marklund, Maja, et al.
(author)
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Spatio-temporal analysis of prostate tumors in situ suggests the pre-existence of ADT-resistance
-
Other publication (other academic/artistic)abstract
- The molecular mechanisms by which potentially lethal castration-resistant prostate cancer emerge in advanced metastatic prostate cancer are still poorly understood. Intratumor heterogeneity is believed to contribute to the fact that a majority of affected men succumb to the disease within a few years. In this study, we will challenge the conventional notion that castration-resistant prostate cancer cells evolve as a consequence of treatment. To examine the temporal aspects of resistance, we analyze tumor heterogeneity in core needle biopsies collected pre-and post-treatment. By doing so, we are able to couple clinical responsiveness and morphological information such as Gleason score to transcriptome- wide data. Our data-driven analysis of transcriptomes identified several distinct intratumoral cell populations, characterized by their unique gene expression profiles. Strikingly, certain minor cell populations present before treatment exhibited gene expression profiles that matched those of resistant tumor cell clusters. Such resistant clusters were confirmed by the localization of the androgen receptor to the nuclei in cancer cells present after treatment. Our data also demonstrate that stromal cells adjacent to resistant tumor factors do not express AR before treatment (or after), which can be used to increase the power in predicting resistant tumors.
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| 14. |
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| 15. |
- Needham, E. J., et al.
(author)
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Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses
- 2022
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:11, s. 4097-4107
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Journal article (peer-reviewed)abstract
- COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible. Needham et al. reveal elevations in blood biomarkers of brain injury in patients hospitalised with COVID-19. The changes, which were severity-dependent, were associated with dysregulated immune responses including increases in pro-inflammatory cytokines and autoantibodies. Ongoing active brain injury could still be seen months after infection.
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| 16. |
- Scharf, Lydia, et al.
(author)
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Longitudinal single-cell analysis of SARS-CoV-2-reactive B cells uncovers persistence of early-formed, antigen specific clones.
- 2023
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In: JCI insight. - : American Society for Clinical Investigation. - 2379-3708. ; 8:1
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Journal article (peer-reviewed)abstract
- Understanding persistence and evolution of B cell clones after COVID-19 infection and vaccination is crucial for predicting responses against emerging viral variants and optimizing vaccines. Here, we collected longitudinal samples from severe COVID-19 patients every third to seventh day during hospitalization and every third month after recovery. We profiled the antigen-specific immune cell dynamics by combining single cell RNA-Seq, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE)-Seq, B cell receptor (BCR)-Seq with oligo-tagged antigen baits. While the proportion of Spike Receptor Binding Domain-specific memory B cells (MBC) increased from 3 months after infection, the other Spike- and Nucleocapsid-specific B cells remained constant. All patients showed ongoing class switching and sustained affinity maturation of antigen specific cells, which was not significantly increased early after vaccine. B cell analysis revealed a polyclonal response with limited clonal expansion; nevertheless, some clones detected during hospitalization, as plasmablasts, persisted for up to one year, as MBC. Monoclonal antibodies derived from persistent B cell families increased their binding and neutralization breadth and started recognizing viral variants by 3 months after infection. Overall, our findings provide important insights into the clonal evolution and dynamics of antigen specific B cell responses in longitudinally sampled COVID-19 infected patients.
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| 17. |
- Sourander, Birger, et al.
(author)
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No effect of remdesivir or betamethasone on upper respiratory tract SARS-CoV-2 RNA kinetics in hospitalised COVID-19 patients: a retrospective observational study
- 2022
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In: Infectious Diseases. - : Informa UK Limited. - 2374-4235 .- 2374-4243. ; 54:10, s. 703-712
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Journal article (peer-reviewed)abstract
- Background The viral kinetics of SARS-CoV-2 has been considered clinically important. While remdesivir and corticosteroids are recommended for COVID-19 patients requiring oxygen support, there is a limited number of published reports on viral kinetics in hospitalised patients with COVID-19 treated with remdesivir or corticosteroids. Methods We conducted a retrospective study by collecting longitudinal samples from the nasopharynx/throat of 123 hospitalised patients (median age 55 years, 74% male) with COVID-19, to evaluate the effects of remdesivir and corticosteroid treatment on viral RNA levels. The subjects were divided into four groups: those receiving remdesivir (n = 25), betamethasone (n = 41), both (n = 15), or neither (n = 42). Time to viral RNA clearance was analysed using Kaplan-Meier plots, categorical data were analysed using Fisher's exact test, and Kruskal-Wallis for continuous data. Viral RNA decline rate was analysed using a mixed effect model. Results We found no significant difference in SARS-CoV-2 RNA decline rate or time to SARS-CoV-2 RNA clearance between the groups. Moreover, clinical status at baseline was not correlated with time to viral clearance. Conclusions Since SARS-CoV-2 RNA kinetics was not affected by treatment, repeated sampling from the upper respiratory tract cannot be used to evaluate treatment response.
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| 18. |
- Yilmaz, Aylin, 1974, et al.
(author)
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Upper respiratory tract levels of SARS-CoV-2 RNA and duration of viral RNA shedding do not differ between patients with mild and severe/critical COVID-19.
- 2021
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In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 223:1, s. 15-18
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Journal article (peer-reviewed)abstract
- This study reports longitudinal viral RNA loads from nasopharynx/throat in patients with mild and severe/critical COVID-19. We also investigated whether the duration of symptoms correlated with the duration of viral RNA shedding. A total of 56 patients were included. The highest viral loads occurred early after onset of symptoms. Neither the viral RNA loads in the upper respiratory tract, nor the time to viral RNA clearance differed between patients with mild or severe/critical disease. There was a moderate correlation between number of days with symptoms and number of days with viral RNA shedding in patients with mild COVID-19.
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| 19. |
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