Liminality in Practice: A Case study in Life Sciences Research

Contemporary health challenges (e.g. diabetes, climate change, antimicrobial resistance) are underpinned by complex interrelationships between behavioral, cultural, social, environmental and biological processes. Current experimental systems are only partially relevant to the problems they investigate, but aspirations to embed interdisciplinary working and community engagement into life scientists’ work inresponse to this partiality have proven difficult in practice. This paper explores one UK university-based life sciences initiative as it seeks to develop modes of working which respond to this complexity. Drawing on ‘liminal hotspots’ as a sensitizing concept, we explore how participating academics articulate complex problems, knowledge-making, interdisciplinary working and community engagement. Our analysis shows they become recurrently ‘trapped’ (institutionally and epistemologically) between fixed/universalized cosmologies of biology/disease, and more contemporary cosmologies in which biology and disease are conceptualized as situated and evolving. Adopting approaches to community organizing based on ‘process pragmatism’ we propose ways in which life scientists might radically reorganise their practice and move beyond current limiting enactments of interdisciplinary and community engaged working. In doing so we claim that the relevance and ‘humanness’ of life scienceresearch will be increased

Thiopurine Treatment in Ulcerative Colitis: A Critical Review of the Evidence for Current Clinical Practice

Background: Due to toxicity problems and controversial evidence, thiopurine use in ulcerative colitis (UC) has faced a lot of criticism. We present a critical review of the literature on efficacy of thiopurines in UC. Methods: Studies evaluating therapeutic efficacy of thiopurine remission induction and/or maintenance treatment in UC were identified using the Cochrane Library, MEDLINE, and EMBASE. Results: Out of 5 randomized trials on thiopurine induction treatment, 3 demonstrated a significant effect of thiopurine treatment vs mesalamine or placebo in steroid-dependent UC patients: (1) lower endoscopic activity scores, (2) higher clinical remission rates, and (3) more patients who discontinued steroids. Two found no significant difference in clinical and endoscopic remission of azathioprine compared with sulfasalazine or placebo in patients with active UC. Out of 7 randomized trials on thiopurine maintenance treatment, 4 demonstrated significant higher clinical and endoscopic remission rates in thiopurine-treated patients compared with placebo or mesalamine. Three found no significant difference in clinical and endoscopic remission of thiopurine maintenance treatment compared with sulfasalazine or placebo. Conclusions: All studies that investigated thiopurine treatment in UC had shortcomings, such as lack of sufficient power, no use of blinding, allowed concomitant treatment with steroids, and no endoscopy to confirm active disease at study entry or to evaluate therapeutic efficacy. Hence, current clinical practice of thiopurine treatment in UC is based on minimal and controversial evidence. This underscores the need for clinical studies with sufficient power and objective end points in order to determine efficacy of thiopurines in UC

The Simple Cholestatic Complaints Score is a valid and quick patient-reported outcome measure in primary sclerosing cholangitis

Background: Measuring symptoms and disease burden in patients with primary sclerosing cholangitis (PSC) is increasingly important for daily practice and clinical trials. The Simple Cholestatic Complaints Score (SCCS) is a four-item questionnaire, that measures cholestatic symptoms (pruritus, fatigue, RUQ abdominal pain and fever) in PSC patients. The aim of this study was to evaluate reliability and validity of SCCS in a Dutch population. Methods: The study population consisted of 212 patients from the Dutch prospective PSC registry. Data were collected via digital surveys. Reliability was evaluated by internal consistency and reproducibility. Construct-, criterion- and discriminant validity were determined. The ability to detect clinical change with SCCS was evaluated in patients who underwent endoscopic intervention. Simple Cholestatic Complaints Score collected by email and by a mobile application were compared. Results: A total of 153 patients completed the questionnaire. Internal consistency was moderate and increased to 0.71 after removal of the fever item. Test-re-test reproducibility was high (intraclass correlation coefficient = 0.96). Criterion validity was good (all > 0.82). Construct validity was in line with a priori hypothesized correlations in 80%. SCCS was able to differentiate between clinically different groups. There was no difference between inflammatory bowel disease (IBD) and non-IBD patients. Simple Cholestatic Complaints Score was responsive to change after endoscopic intervention in successfully treated patients. Simple Cholestatic Complaints Score measurement by digital questionnaire and a mobile application was comparable. Conclusion: The SCCS is a valid instrument to measure cholestatic symptoms in PSC patients. Because of its quick and easy to use properties it is suitable for frequent monitoring of symptoms in clinical trials and daily practice

Intestinal ultrasound is accurate to determine endoscopic response and remission in patients with moderate to severe ulcerative colitis: a longitudinal prospective cohort study.

BACKGROUND AND AIMS Intestinal ultrasound (IUS) is non-invasive, cost-effective and accurate to determine disease activity in ulcerative colitis (UC). In this study we prospectively evaluated IUS for treatment response in a longitudinal cohort by using endoscopy and histology as gold standards. METHODS Consecutive patients with moderate-to-severe UC (endoscopic Mayo score (EMS)≥2) starting tofacitinib treatment were included. Patients were evaluated at baseline and after 8 weeks of tofacitinib induction by means of clinical, biochemical, endoscopic (EMS and ulcerative colitis endoscopic index for severity (UCEIS)), histological (Robarts Histopathologic Index (RHI)) and IUS assessments. Readers of IUS, endoscopy and histology were blinded for all other outcomes. The primary outcome was difference in bowel wall thickness (BWT) for endoscopic improvement versus no endoscopic improvement. Endoscopic remission was defined as EMS=0, improvement as EMS≤1 and response as a decrease of EMS≥1. RESULTS Thirty patients were included with 27 patients completing follow-up. BWT correlated with EMS (ρ=0.68, p<0.0001), UCEIS (ρ=0.73, p<0.0001) and RHI (ρ=0.49, p=0.002) at both time-points. BWT in the sigmoid was lower in patients with endoscopic remission (1.4mm vs 4.0mm, p=0.016), endoscopic improvement (1.8mm vs 4.5mm, p<0.0001) and decrease in BWT was more pronounced in patients with endoscopic response (-58.1% vs -13.4%, p=0.018). The most accurate cut-off values for BWT were 2.8 mm (AUC:0.87) for endoscopic remission, 3.9 mm (AUC:0.92) for improvement and decrease of 32% (AUC:0.87) for response. The submucosa was the most responsive wall layer. CONCLUSION IUS, importantly BWT as the single most important parameter, is highly accurate to detect treatment response when evaluated against endoscopic outcomes

Intestinal Ultrasound Is Accurate to Determine Endoscopic Response and Remission in Patients With Moderate to Severe Ulcerative Colitis: A Longitudinal Prospective Cohort Study

Background & Aims: Intestinal ultrasound (IUS) is noninvasive, cost-effective, and accurate to determine disease activity in ulcerative colitis (UC). In this study, we prospectively evaluated IUS for treatment response in a longitudinal cohort by using endoscopy and histology as gold standards. Methods: Consecutive patients with moderate to severe UC (endoscopic Mayo score [EMS] ≥2) starting tofacitinib treatment were included. Patients were evaluated at baseline and after 8 weeks of tofacitinib induction by means of clinical, biochemical, endoscopic (EMS and UC endoscopic index for severity), histologic (Robarts Histopathologic Index) and IUS assessments. Readers of IUS, endoscopy, and histology were blinded for all other outcomes. The primary outcome was difference in bowel wall thickness (BWT) for endoscopic improvement vs no endoscopic improvement. Endoscopic remission was defined as EMS = 0, improvement as EMS ≤1, and response as a decrease of EMS ≥1. Results: Thirty patients were included, with 27 patients completing follow-up. BWT correlated with EMS (ρ = 0.68, P <.0001), UC endoscopic index for severity (ρ = 0.73, P <.0001) and Robarts Histopathologic Index (ρ = 0.49, P =.002) at both time points. BWT in the sigmoid was lower in patients with endoscopic remission (1.4 mm vs 4.0 mm, P =.016), endoscopic improvement (1.8 mm vs 4.5 mm, P <.0001) and decrease in BWT was more pronounced in patients with endoscopic response (−58.1% vs −13.4%, P =.018). The most accurate cutoff values for BWT were 2.8 mm (area under the curve [AUC] 0.87) for endoscopic remission, 3.9 mm (AUC 0.92) for improvement, and decrease of 32% (AUC 0.87) for response. The submucosa was the most responsive wall layer. Conclusion: IUS, importantly BWT as the single most important parameter, is highly accurate to detect treatment response when evaluated against endoscopic outcomes

Intestinal Ultrasound Is Accurate to Determine Endoscopic Response and Remission in Patients With Moderate to Severe Ulcerative Colitis: A Longitudinal Prospective Cohort Study

Background & Aims: Intestinal ultrasound (IUS) is noninvasive, cost-effective, and accurate to determine disease activity in ulcerative colitis (UC). In this study, we prospectively evaluated IUS for treatment response in a longitudinal cohort by using endoscopy and histology as gold standards. Methods: Consecutive patients with moderate to severe UC (endoscopic Mayo score [EMS] ≥2) starting tofacitinib treatment were included. Patients were evaluated at baseline and after 8 weeks of tofacitinib induction by means of clinical, biochemical, endoscopic (EMS and UC endoscopic index for severity), histologic (Robarts Histopathologic Index) and IUS assessments. Readers of IUS, endoscopy, and histology were blinded for all other outcomes. The primary outcome was difference in bowel wall thickness (BWT) for endoscopic improvement vs no endoscopic improvement. Endoscopic remission was defined as EMS = 0, improvement as EMS ≤1, and response as a decrease of EMS ≥1. Results: Thirty patients were included, with 27 patients completing follow-up. BWT correlated with EMS (ρ = 0.68, P <.0001), UC endoscopic index for severity (ρ = 0.73, P <.0001) and Robarts Histopathologic Index (ρ = 0.49, P =.002) at both time points. BWT in the sigmoid was lower in patients with endoscopic remission (1.4 mm vs 4.0 mm, P =.016), endoscopic improvement (1.8 mm vs 4.5 mm, P <.0001) and decrease in BWT was more pronounced in patients with endoscopic response (−58.1% vs −13.4%, P =.018). The most accurate cutoff values for BWT were 2.8 mm (area under the curve [AUC] 0.87) for endoscopic remission, 3.9 mm (AUC 0.92) for improvement, and decrease of 32% (AUC 0.87) for response. The submucosa was the most responsive wall layer. Conclusion: IUS, importantly BWT as the single most important parameter, is highly accurate to detect treatment response when evaluated against endoscopic outcomes

Systematic review with meta-analysis: risk factors for thiopurine-induced leukopenia in IBD

Background: Thiopurine-induced leukopenia, a frequently observed and potentially life-threatening adverse event, complicates the clinical management of IBD patients. Aim: To assess risk factors for thiopurine-induced leukopenia in IBD. Methods: MEDLINE, EMBASE, BIOSIS and Cochrane library were searched for studies reporting at least one risk factor for thiopurine-induced leukopenia. Pooled odds ratio (OR) was calculated for each potential risk factor using a random effects model. Studies that were not eligible for meta-analysis were described qualitatively. Results: Seventy articles were included, 34 (11 229 patients) were included in meta-analyses. A significantly higher thiopurine-induced leukopenia risk was found for TPMT (OR 3.9, 95% [CI] 2.5-6.1) and for NUDT15 R139C (OR 6.9, 95% CI 5.2-9.1), G52A (OR 3.2, 95% CI 1.3-7.9) and 36_37ins/delGGAGTC variant carriers (OR 5.6, 95% CI 2.8-11.4). A potential association between high 6-thioguanine nucleotides (6-TGN) or 6-methylmercaptopurine (6-MMP) levels and leukopenia was observed, since most studies reported higher metabolite levels in leukopenic patients (6-TGN: 204-308 (Lennard method) and 397 (Dervieux method), 6-MMP: 4020-10 450 pmol/8 x 108 RBC) compared to controls (6-TGN: 170-212 (Lennard method) and 269 (Dervieux method), 6-MMP: 1025-4550 pmol/8 x 108 RBC). Conclusions: TPMT and NUDT15 variants predict thiopurine-induced leukopenia. High 6-TGN and 6-MMP levels might induce leukopenia, although exact cut-off values remain unclear. Potential preventive measures to reduce the risk of thiopurine-induced leukopenia include pre-treatment TPMT and NUDT15 genotyping. Routine thiopurine metabolite measurement might be efficient, yet cut-off levels must be validated in advance

Histological Outcomes And Jak-Stat Signalling In Ulcerative Colitis Patients Treated With Tofacitinib.

BACKGROUND AND AIMS Histological outcomes and JAK-STAT signaling were assessed in a prospective ulcerative colitis (UC) patient cohort after 8 weeks treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor. METHODS Forty UC patients received tofacitinib 10 mg twice daily for 8 weeks. Treatment response was defined as histo-endoscopic mucosal improvement (HEMI). Histological remission was defined as a Robarts Histopathology Index (RHI) ≤3 points and histological response as 50% decrease in RHI. Mucosal expression of JAK1-3, Tyrosine kinase 2 (TYK2) and total signal transducer and activator of transcription (STAT) 1-6 were assessed using immunohistochemistry (IHC). RESULTS At baseline, the median RHI was 14 (interquartile range (IQR) 10-19). Twenty-six of 40 (65%) patients had severe endoscopic disease (endoscopic Mayo score 3) and 31/40 (78%) failed prior anti-TNF treatment. At week 8, 15 patients (38%) had HEMI, 23 patients (58%) histological remission and 34 (85%) histological response. RHI decreased by a median of 14 points (IQR 9-21) in responders (p<0.001) and by 6 points (IQR 0-13) in non-responders (p=0.002). STAT1, STAT3 and STAT5 expression levels decreased significantly in the whole cohort. Responders had lower week 8 STAT1 expression levels compared to non-responders (0.2%, IQR 0.1-2.8 vs 4.3%, IQR 1.2-11.9, p=0.001), suggesting more profound STAT1 blockade. A trend of higher baseline JAK2 expression was observed in tofacitinib non-responders (2.7%, IQR 0.1-7.7) compared to responders (0.4%, IQR 0.1-2.1). CONCLUSIONS Tofacitinib treatment resulted in histological improvement in the majority of UC patients and a substantial decrease of STAT1, STAT3 and STAT5 expression. HEMI was associated with more profound suppression of STAT1

Mercaptopurine for the treatment of ulcerative colitis - a randomised placebo-controlled trial.

BACKGROUND AND AIMS Scepticism about the efficacy of thiopurines for ulcerative colitis (UC) is rising.This study aimed to evaluate mercaptopurine treatment for UC. METHODS In this prospective, randomised, double-blind, placebo-controlled trial, patients with active UC, despite treatment with 5-aminosalicylates (5-ASA), were randomised for therapeutic drug monitoring (TDM)-guided mercaptopurine treatment or placebo for 52 weeks. Corticosteroids were given in the first eight weeks and 5-ASA was continued. Proactive metabolite-based mercaptopurine and placebo dose adjustments were applied from week six onwards by unblinded clinicians. The primary endpoint was corticosteroid-free clinical remission and endoscopic improvement (total Mayo score ≤2 points and no item >1) at week 52 in an intention-to-treat analysis. RESULTS Between December 2016 and April 2021, 70 patients were screened and 59 were randomised at six centres. In the mercaptopurine group, 16/29 (55.2%) patients completed the 52-week study, compared to 13/30 (43.3%) on placebo. The primary endpoint was achieved by 14/29 (48.3%) patients on mercaptopurine and 3/30 (10%) receiving placebo (Δ=38.3%, 95% CI 17.1-59.4, p=0.002). Adverse events occurred more frequently with mercaptopurine (808.8 per 100 patient years) compared to placebo (501.4 per 100 patient years). Five serious adverse events occurred; four on mercaptopurine and one on placebo. TDM-based dose adjustments were executed in 22/29 (75.9%) patients, leading to lower mercaptopurine doses at week 52 compared to baseline. CONCLUSIONS Optimised mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at one year following corticosteroid induction treatment in UC patients. More adverse events occurred in the mercaptopurine group