Early management of acute severe UC in the biologics era: development and international validation of a prognostic clinical index to predict steroid response.

OBJECTIVES: We aimed to determine whether changes in acute severe colitis (ASC) management have translated to improved outcomes and to develop a simple model predicting steroid non-response on admission. DESIGN: Outcomes of 131 adult ASC admissions (117 patients) in Oxford, UK between 2015 and 2019 were compared with data from 1992 to 1993. All patients received standard treatment with intravenous corticosteroids and endoscopic disease activity scoring (Ulcerative Colitis Endoscopic Index of Severity (UCEIS)). Steroid non-response was defined as receiving medical rescue therapy or surgery. A predictive model developed in the Oxford cohort was validated in Australia and India (Gold Coast University Hospital 2015-2020, n=110; All India Institute of Medical Sciences, New Delhi 2018-2020, n=62). RESULTS: In the 2015-2019 Oxford cohort, 15% required colectomy during admission vs 29% in 1992-1993 (p=0.033), while 71 (54%) patients received medical rescue therapy (27% ciclosporin, 27% anti-tumour necrosis factor, compared with 27% ciclosporin in 1992-1993 (p=0.0015). Admission C reactive protein (CRP) (false discovery rate, p=0.00066), albumin (0.0066) and UCEIS scores (0.015) predicted steroid non-response. A four-point model was developed involving CRP of ≥100 mg/L (one point), albumin of ≤25 g/L (one point), and UCEIS score of ≥4 (1 point) or ≥7 (2 points). Patients scoring 0, 1, 2, 3 and 4 in the validation cohorts had steroid response rates of 100, 75.0%, 54.9%, 18.2% and 0%, respectively. Scoring of ≥3 was 84% (95% CI 0.70 to 0.98) predictive of steroid failure (OR 11.9, 95% CI 10.8 to 13.0). Colectomy rates in the validation cohorts were were 8%-11%. CONCLUSIONS: Emergency colectomy rates for ASC have halved in 25 years to 8%-15% worldwide. Patients who will not respond to corticosteroids are readily identified on admission and may be prioritised for early intensification of therapy.

Pain, well-being, body image and cosmesis: a comparison of single-port and four-port laparoscopic cholecystectomy.

BACKGROUND: This study aims to compare post-operative pain, well-being, body image and cosmesis in SILS cholecystectomy and four-port laparoscopic cholecystectomy (FPLC). MATERIAL AND METHODS: Forty-two consecutive patients (15 SILS, 27 FPLC) undergoing elective cholecystectomy were included in the study. Peri-operative pain, well-being, body image and cosmesis were evaluated using validated assessment tools. RESULTS: Significantly lower pain scores were reported one week post-operatively in the SILS group (5.6 vs 8.3; p = 0.035). No significant difference was found in analgesic requirements, physical or mental well-being at any time interval. Significantly higher (favourable) body image questionnaire scores were reported in the SILS group at one week (5.4 v 4.5; p < 0.01), two weeks (5.6 vs 4.8; p < 0.01) and one month (5.7 vs 5.0; p < 0.01) post-operatively. CONCLUSION: SILS patients have significantly reduced one-week pain scores and there was no significant difference in well-being between the two groups. Patients who underwent SILS had improved body image and cosmesis. If both techniques are found to be equivalent concerning safety, cost, learning curve and availability, SILS may play a key role in the new era of patient choice.

Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis.

The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.

Pathogenesis of Fistulating Crohn's Disease: A Review.

Sustained, transmural inflammation of the bowel wall may result in the development of a fistula in Crohn's disease (CD). Fistula formation is a recognized complication and cause of morbidity, occurring in 40% of patients with CD. Despite advanced treatment, one-third of patients experience recurrent fistulae. Development of targeting treatment for fistulae will be dependent on a more in depth understanding of its pathogenesis. Presently, pathogenesis of CD-associated fistulae remains poorly defined, in part due to the lack of accepted in vitro tissue models recapitulating the pathogenic cellular lesions linked to fistulae and limited in vivo models. This review provides a synthesis of the existing knowledge of the histopathological, immune, cellular, genetic, and microbial contributions to the pathogenesis of CD-associated fistulae including the widely accredited contribution of epithelial-to-mesenchymal transition, upregulation of matrix metalloproteinases, and overexpression of invasive molecules, resulting in tissue remodeling and subsequent fistula formation. We conclude by exploring how we might utilize advancing technologies to verify and broaden our current understanding while exploring novel causal pathways to provide further inroads to future therapeutic targets.

Geography Influences Susceptibility to SARS-CoV-2 Serological Response in Patients With Inflammatory Bowel Disease: Multinational Analysis From the ICARUS-IBD Consortium.

BACKGROUND: Beyond systematic reviews and meta-analyses, there have been no direct studies of serological response to COVID-19 in patients with inflammatory bowel disease (IBD) across continents. In particular, there has been limited data from Asia, with no data reported from India. The ICARUS-IBD (International study of COVID-19 Antibody Response Under Sustained immunosuppression in IBD) consortium assessed serological response to SARS-CoV-2 in patients with IBD in North America, Europe, and Asia. METHODS: The ICARUS-IBD study is a multicenter observational cohort study spanning sites in 7 countries. We report seroprevalence data from 2303 patients with IBD before COVID-19 vaccination between May 2020 and November 2021. SARS-CoV-2 anti-spike and anti-nucleocapsid antibodies were analyzed. RESULTS: The highest and lowest SARS-CoV-2 anti-spike seropositivity rates were found in Asia (81.2% in Chandigarh and 57.9% in Delhi, India; and 0% in Hong Kong). By multivariable analysis, country (India: odds ratio [OR], 18.01; 95% confidence interval [CI], 12.03-26.95; P < .0001; United Kingdom: OR, 2.43; 95% CI, 1.58-3.72; P < .0001; United States: OR, 2.21; 95% CI, 1.27-3.85; P = .005), male sex (OR, 1.46; 95% CI, 1.07-1.99; P = .016), and diabetes (OR, 2.37; 95% CI, 1.04-5.46; P = .039) conferred higher seropositivity rates. Biological therapies associated with lower seroprevalence (OR, 0.22; 95% CI, 0.15-0.33; P < .0001). Multiple linear regression showed associations between anti-spike and anti-nucleocapsid titers with medications (P < .0001) but not with country (P = .3841). CONCLUSIONS: While the effects of medications on anti-SARS-CoV-2 antibody titers in patients with IBD were consistent across sites, geographical location conferred the highest risk of susceptibility to serologically detectable SARS-CoV-2 infection. Over half of IBD patients in India were seropositive prior to vaccination. These insights can help to inform shielding advice, therapeutic choices, and vaccine strategies in IBD patients for COVID-19 and future viral challenges.

In this multinational study of SARS-CoV-2 seroprevalence prior to vaccination, including the first data from India, where over half of patients seroconverted, geographical location conferred the highest risk of susceptibility to serologically detectable infection.

A new visual design language for biological structures in a cell.

As part of a project to build a spatiotemporal model of the pancreatic ß-cell, we are creating an immersive experience called "World in a Cell" that can be used to integrate and create new educational tools. To do this, we have developed a new visual design language that uses tetrahedral building blocks to express the structural features of biological molecules and organelles in crowded cellular environments. The tetrahedral language enables more efficient animation and user interaction in an immersive environment.

A randomised comparative study evaluating learning curves of novices in a basic single-incision laparoscopic surgery task.

OBJECTIVE: There is currently no objective quantification of the temporal changes in performance associated with a novice surgeon learning single-incision laparoscopic surgery (SILS) operative tasks. Analysing learning curves allows us to objectively quantify performance. The aim was to evaluate if the rate of learning and ultimate proficiency level reached in SILS when using straight or articulating instruments is different to conventional laparoscopy and if training in laparoscopy influences learning or proficiency for SILS. DESIGN AND SETTING: Thirty-six surgically naive medical students were randomised to complete the validated peg transfer task over 50 repetitions using a conventional laparoscopic set-up, SILS set-up with straight instruments or articulated instruments or SILS set-up after having reached proficiency using a conventional laparoscopy. RESULTS: There was a significant increased overall proficiency between the group trained in conventional laparoscopy and all other groups (p < 0.01), with no difference between the other groups. There was no difference in the rate of learning between the groups. There was no difference in the ultimate proficiency level (p = 0.671) or rate of learning (p = 0.63) when using straight or articulating instruments. There was no difference in ultimate proficiency level (p = 0.59) or learning rate (p = 0.219) seen in the SILS group that had prior training on the task with a conventional laparoscopic set-up. CONCLUSIONS: The results of this study indicate that the proficiency reached using a conventional laparoscopic set-up cannot be matched using a SILS configuration for the novice surgeon and that the choice of straight or articulated instruments as well as previous laparoscopic training does not confer an advantage in this basic task.

Evaluating systemic stress response in single port vs. multi-port laparoscopic cholecystectomy.

BACKGROUND AND AIMS: Acute-phase proteins and inflammatory cytokines mediate measurable responses to surgical trauma, which are proportional to the extent of tissue injury and correlate with post-operative outcome. By comparing systemic stress following multi-port (LC) and single-incision laparoscopic cholecystectomy (SILC), we aim to determine whether reduced incision size induces a reduced stress response. METHODS: Thirty-five consecutive patients were included, 11 underwent SILC (mean ± SEM; age 44.8 ± 3.88 year; BMI 27 ± 1.44 kg/m(2)) and 24 underwent LC (56.17 ± 2.80 year; 31.72 ± 1.07 kg/m(2), p < 0.05). Primary endpoint measures included levels of interleukin-6 and C-reactive protein measured pre- and post-operatively. Length-of-stay (LOS) and postoperative morbidity were secondary endpoints. RESULTS: No statistically significant differences were found between SILC and LC for interleukin-6 and C-reactive protein levels, LOS and duration of surgery. There was also no correlation between systemic stress response and operative parameters. There were no intra-operative complications. CONCLUSION: SILC appears to be a safe, feasible technique with potential advantages of cosmesis, reduced incisional pain, and well-being recommending its use. These data indicate no difference in systemic stress and morbidity between SILC and LC. A larger, multi-centred, randomised prospective trial is warranted to further investigate and confirm this finding.