Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome

Objectives Clinical presentation of primary Sjögren’s syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints. Methods We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls. Results We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10−62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS. Conclusion Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.publishedVersio

Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial

BackgroundPriming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca).MethodsCom-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020–005085–33).FindingsBetween Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77–89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2–ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1–1·8) for homologous BNT162b2, 1·5 (1·2–1·9) for ChAdOx1 nCoV-19–BNT162b2, 1·6 (1·3–2·1) for BNT162b2–ChAdOx1 nCoV-19, and 2·4 (1·7–3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17–0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19–BNT162b2 were up to 80% less reactogenic than 4-week schedules.InterpretationThese data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals

Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial

Background: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. Methods: Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. Findings: Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. Interpretation: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. Funding: UK Vaccine Task Force and National Institute for Health Research

Den estetiska erfarenheten som erfarandets fulländning : en kritisk läsning av John Deweys estetiska erfarenhetsbegrepp i Art as Experience.

The purpose of this article is to critically explore the concept ofaesthetic experience, as discussed and developed by John Dewey inhis work Art as Experience (1934). This is done by examining thelinks between Dewey’s concept of experience in general, and itsepistemological basis, and his specific concept of aesthetic experience. Special attention is paid to Dewey’s distinction between art asproduct and art as work, and what function, according to Dewey,art might have for individuals and communities. Finally, the educational implications are discussed, particularly in relation to theabove-mentioned distinction in Dewey’s theory of aesthetics

Children's Democratic Experiences in a Collective Writing Process : Analysing Classroom Interaction in Terms of Deliberation

The aim of this study is twofold: firstly, it aims to explore the interactional conditions in terms of democratic qualities constituted in collective writing in a primary school classroom; and secondly, it aims to examine whether a set of deliberative criteria is fruitful as an analytical tool when studying classroom interaction. Theoretically, I turn to New Literacy Studies for understanding the writing classroom as a literacy practice and the actual (collective) writing as literacy events. The study has an ethnographic approach in which classroom observations were conducted during a collective writing process involving six nine-year-old children and their teacher. The observations included, two lessons, divided into 3 hours, which were observed, videotaped, and transcribed. The teacher had planned for a strict interactional or didactical order during the collective writing in which the children were to respond individually. However, the children responded in a different manner by starting a vivid dialogue in which they negotiated both the form and the content of the story. The analysis shows some deliberative qualities in this classroom interaction, while some other qualities were not evident. Furthermore, the analysis showed that the set of deliberative criteria was useful in visualizing both existing deliberative qualities in the interaction and the potential for developing such qualities.Open Access APC beslut 8/2017</p

Samtalsgenrer i gymnasieskolans litteraturundervisning : en ämnesdidaktisk studie

The aim of this dissertation is to analytically discern different conversational genres within the teaching of literature, organized within the framework of the two school subjects in which Swedish is taught in upper secondary school, and to place this teaching of literature in a historical context by relating it to different conceptions of the Swedish subject. To be able to achieve this aim, a curriculum studies approach is combined with an ethnographical one. The ethnographical part of the study was conducted as a classroom study, including five different classes and teachers talking about literature, which took place during the school year 2003/2004 at three different schools in the middle of demographical Sweden. This part of the study also involved qualitative interviews with teachers and students concerning different factors which might have an effect on these conversations. The conversations of the study can be described as a part of the every-day-life of the teaching of those subjects, as the teachers organised these conversations in a way that they usually organise conversations of literature in their classes. However, what the teachers meant by talking about literature appeared to differ among them so radically that these conversations could be analytically discerned as four different conversational genres: The Teaching Examination, Text Oriented Talk, Culturally Oriented Talk, and Informal Book Talk. These four conversational genres are possible to analytically discern using the didactical tool, the analysis of conversational genres, which is developed in the dissertation in relation to Michail Bakhtin’s theory of speech genres. The curriculum part of the study comprises an analysis in three steps to place the teaching of literature in a historical context. In the first step national syllabuses for the subjects Swedish and Swedish as a second language are analysed. In the second step local syllabuses for the subjects are analysed. Finally, in the third step, the teachers’ thoughts, deliberations and ideals forming their teaching of literature are analysed. The teaching where conversational genres have been analytically discerned could then be related to different conceptions of the subject Swedish: Swedish as a Higher Subject of Bildung, Swedish as a Proficiency Subject, and Swedish as an Experience-based Subject. The analyses and discussions in the dissertation contribute to the discussions in the field of Subject-Didactics on the role of literature and conversation within the subjects of Swedish and Swedish as a Second language. Another contribution of the dissertation is the didactical tool, the analysis of conversational genres, which might be used by researchers and teachers for analysis and reflection on conversations in teaching

Den estetiska erfarenheten som erfarandets fulländning : en kritisk läsning av John Deweys estetiska erfarenhetsbegrepp i Art as Experience.

The purpose of this article is to critically explore the concept ofaesthetic experience, as discussed and developed by John Dewey inhis work Art as Experience (1934). This is done by examining thelinks between Dewey’s concept of experience in general, and itsepistemological basis, and his specific concept of aesthetic experience. Special attention is paid to Dewey’s distinction between art asproduct and art as work, and what function, according to Dewey,art might have for individuals and communities. Finally, the educational implications are discussed, particularly in relation to theabove-mentioned distinction in Dewey’s theory of aesthetics