A study of the pathologies of performativity

Temaet for denne afhandling er en undersøgelse af tre historiske ’formationer’ organiseret omkring en ’ting’ i kroppen i melankoliens brede og farverige historie i et forsøg på at skabe baggrund for en filosofisk undersøgelse af sammenhængen mellem patologi, arbejde og performativitet i samtiden. I denne forstand er der tale om et stykke filosofisk grundforskning, der forsøger at etablere og åbne et felt for mødet mellem de klassiske, filosofiske discipliner, og temaer i organisationsteori og ledelsesfilosofi

Om viden, socialitet og immaterialitet

Om viden, socialitet og immaterialite

Intensified anti-TNF treatment downregulates the phenotype in ulcerative colitis: a 13-year prospective follow-up study

BackgroundModerate to severe ulcerative colitis (UC) is generally treated with a step-up algorithm from 5-aminosalicylic acid (5-ASA) to biological agents. There is no general recommendation if or when to de-escalate or discontinue biological therapy. In this study, we performed biological therapy with anti-tumor necrosis factor (TNF) treatment to endoscopic remission followed by discontinuation of therapy. This is a 13- year follow-up study performed for this treatment algorithm.AimThis study aimed to assess whether the treatment algorithm outlined above influences the UC phenotype toward a milder form and identify potential biomarkers for altering the disease phenotype.MethodsPatients with moderate to severe UC were enrolled from 2004 to 2015 and followed up until 2023 to evaluate disease outcomes. Patients were categorized into subgroups based on the highest treatment level required to attain remission: non-biological therapy, biological therapy, or colectomy. Mucosal TNF mRNA expression levels were measured using real-time PCR.ResultsOut of the 116 patients from the original cohort, 71 individuals who had previously undergone anti-TNF treatment to endoscopic remission and subsequently discontinued anti-TNF therapy were included in the present study. Disease outcomes were registered until 2023. By the end of the observation period, 62% of participants were in remission without biological treatment. Among the 71 patients, 39% never experienced a relapse, 23% relapsed but successfully attained remission with untargeted treatment, 18% relapsed and subsequently received a new sequence of biological therapy, and 20% had colectomy. Normalized mucosal TNF mRNA expression was identified as a significant predictor for clinical outcomes.ConclusionMost UC patients transitioned to a milder disease phenotype without requiring biological therapy. Treating to normalize mucosal TNF expression emerges as a potential biomarker, predicting the downregulation of disease severity

Reproducible probe-level analysis of the Affymetrix Exon 1.0 ST array with R/Bioconductor

The presence of different transcripts of a gene across samples can be analysed by whole-transcriptome microarrays. Reproducing results from published microarray data represents a challenge due to the vast amounts of data and the large variety of pre-processing and filtering steps employed before the actual analysis is carried out. To guarantee a firm basis for methodological development where results with new methods are compared with previous results it is crucial to ensure that all analyses are completely reproducible for other researchers. We here give a detailed workflow on how to perform reproducible analysis of the GeneChip Human Exon 1.0 ST Array at probe and probeset level solely in R/Bioconductor, choosing packages based on their simplicity of use. To exemplify the use of the proposed workflow we analyse differential splicing and differential gene expression in a publicly available dataset using various statistical methods. We believe this study will provide other researchers with an easy way of accessing gene expression data at different annotation levels and with the sufficient details needed for developing their own tools for reproducible analysis of the GeneChip Human Exon 1.0 ST Array

Pharmacodynamic mechanisms behind a refractory state in inflammatory bowel disease

Background and aims - Biological therapy for inflammatory bowel disease is efficient in many cases but not all. The underlying molecular mechanisms behind non-response to biological therapy in inflammatory bowel disease are poorly described. Therefore, we aimed to characterize the mucosal cytokine transcript profile in non-immunogenic, non-responder patients with adequate trough level. Material and methods - Patients with ulcerative colitis (UC) (n = 21) and Crohn’s disease (CD) (n = 12) with non-response to biological therapy (anti-tumor necrosis factor (TNF) or vedolizumab) were included. Reference groups were A: untreated patients with UC or CD at debut of disease who had severe 1-year outcome, B: patients with UC or CD treated to endoscopic remission with biological agents, and C: healthy normal controls. Mucosal transcripts of TNF, interleukin (IL)17 and IL23 were measured by reverse transcription real-time quantitative polymerase chain reaction. Results Of the non-responders, 2 out of 12 CD and 1 out of 21 UC patients needed surgery during follow-up. Of the remaining non-responding patients, 8 out of 10 CD and 12 out of 20 UC patients switched biologic treatment. The remaining 2 CD and 8 UC patients continued treatment with the same biological agent with the addition of steroids, immunomodulators (AZA/MTX) and /or local steroids/5ASA. Twelve (8 UC/4 CD) out of 20 IBD patients were still non-responders after changing biological therapy to either anti-TNF (2), vedolizumab (9) or ustekinumab (1). The transcripts of IL17, IL23 and TNF were significantly upregulated in the non-response group compared to normal controls and patients in remission. In UC, 24% of the non-responders had normal mucosal TNF transcript indicating a non-TNF mediated inflammation. No obvious differences in gene expression were observed between primary and secondary non-responders, nor between anti-TNF and vedolizumab non-responders. Conclusions - Mucosal transcripts of IL17 and IL23 are highly associated with non-response to biological therapy, whereas some UC patients may also have a non-TNF mediated inflammatory pathway

Hypo-osmotic stress induces the epithelial alarmin IL-33 in the colonic barrier of ulcerative colitis

Epithelial alarmins are gaining interest as therapeutic targets for chronic infammation. The nuclear alarmin interleukin-33 (IL-33) is upregulated in the colonic mucosa of acute ulcerative colitis (UC) and may represent an early instigator of the infammatory cascade. However, it is not clear what signals drive the expression of IL-33 in the colonic mucosa, nor is the exact role of IL-33 elucidated. We established an ex vivo model using endoscopic colonic biopsies from healthy controls and UC patients. Colonic biopsies exposed to hypo-osmotic medium induced a strong nuclear IL-33 expression in colonic crypts in both healthy controls and UC biopsies. Mucosal IL33 mRNA was also signifcantly increased following hypo-osmotic stress in healthy controls compared to non-stimulated biopsies (fold change 3.9, p-value < 0.02). We observed a modest induction of IL-33 in response to TGF-beta-1 stimulation, whereas responsiveness to infammatory cytokines TNF and IFN-gamma was negligible. In conclusion our fndings indicate that epithelial IL-33 is induced by hypo-osmotic stress, rather than prototypic proinfammatory cytokines in colonic ex vivo biopsies. This is a novel fnding, linking a potent cytokine and alarmin of the innate immune system with cellular stress mechanisms and mucosal infammation

Effects of fecal microbiota transplantation in subjects with irritable bowel syndrome are mirrored by changes in gut microbiome

Irritable bowel syndrome (IBS) is a common disorder of the lower gastrointestinal tract. The pathophysiology is far from settled, but a gut microbial dysbiosis is hypothesized to be a contributing factor. We earlier published a randomized double-blind placebo-controlled clinical trial on fecal microbiota transplantation (FMT) for IBS – the REFIT trial. The present data set describes the engraftment and includes participants from the study who received active FMT; 14 participants with effect of FMT (Effect) and 8 without (No effect). Samples were collected at baseline, after 6 and 12 months. Samples from the transplants (Donor) served as a comparator. In total 66 recipient samples and 17 donor samples were subjected to deep metagenomic sequencing, and taxonomic and functional analyses were performed. Alpha diversity measures showed a significantly increased diversity and evenness in the IBS groups compared to the donors. Taxonomic profiles showed higher relative abundance of phylum Firmicutes, and lower relative abundance of phylum Bacteroidetes, compared to donors at baseline. This profile was shifted toward the donor profile following FMT. Imputed growth rates showed that the resulting growth pattern was a conglomerate of donor and recipient activity. Thirty-four functional subclasses showed distinct differences between baseline samples and donors, most of which were shifted toward a donor-like profile after FMT. All of these changes were less pronounced in the No effect group. We conclude that FMT induces long-term changes in gut microbiota, and these changes mirror the clinical effect of the treatment. The study was registered in ClinicalTrials.gov (NCT02154867)

Governing maximum reindeer numbers in Fennoscandia

Publisher Copyright: © 2022 selection and editorial matter, Tim Horstkotte, Øystein Holand, Jouko Kumpula and Jon Moen.This chapter examines the complexities and challenges in state governance of the maximum permitted number of reindeer in Finland, Norway and Sweden. The common findings regarding the three countries are that (1) maximum permitted numbers of reindeer set by the nation states primarily seem to promote objectives other than those of herders; (2) various contextual aspects (e.g., laws, other land users, trends in science, herding practices and historical developments) partly explain the sustainable maximum permitted numbers; (3) reductionist assessments of pasture – reindeer relations easily neglect the impacts of other land users on condition and availability of pastures, thereby making the assessments biased and stigmatizing herders for alleged overgrazing. The chapter also explores issues related to reindeer numbers that vary across the three countries including (4) herders’ opportunities to participate in knowledge production and resulting decisions over maximum reindeer numbers, (5) clashes between herders’ experience and practice-based knowledge and scientific knowledge on which the definitions of maximum numbers are often based and (6) the ways in which the borders between reindeer herding districts and nation states have implications for the governance of reindeer numbers.Peer reviewe