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Background: Some early genetic events in the development of colorectal adenomas are known, but their relationship to in vivo growth characteristics is uncertain. This study compared in situ size changes and other clinicopathological variables with selected genetic and protein markers. Methods: 56 adenomas (≤10 mm) from 39 patients were analysed for APC, CTNNB1 and K- ras mutations, allelic imbalance on 1p and 18q, microsatellite instability and immunohistochemical expression of HLA-DR, BAX, BCL-2 and Ki-67. For 42 of the adenomas, in situ growth was measured over 3 years. The total number of polyps in each patient was recorded. Results: K- ras was mutated in 8/56 adenomas. None of the regressing adenomas revealed such mutations, compared to 20% in those that maintained or increased their size. Multivariate linear regression analysis showed that tumour growth was higher in females compared to males, and was even higher in the presence of a K- ras mutation. APC mutations were found in 37/56 adenomas. CTNNB1 mutations were found in 2/19 adenomas without APC mutation. Deletions of 1p were found in 12/56 adenomas and, seemingly, most frequent in patients with few tumours. The most frequently expressed protein was BAX (33/41), but neither this nor the other proteins showed associations with an in situ growth pattern. Conclusion: The multivariate linear regression model showed that patient gender and the presence of K- ras mutation had significant effects on tumour growth. The lack of the proliferative stimulus resulting from a K- ras mutation may contribute to the process of adenoma regression. [ABSTRACT FROM AUTHOR]

The current study investigated if physical loads peak on game days and if Bio-Electro-Magnetic-Energy-Regulation (BEMER) therapy is affecting sleep duration and sleep quality on nights related to game nights among elite players in Norwegian women's elite football. The sample included 21 female football players from an elite top series club with a mean age of ~24 years (± 2.8). Sleep was measured every day over a period of 273 consecutive days with a Somnofy sleep monitor based on ultra-wideband (IR-UWB) pulse radar and Doppler technology. The current study was conducted as a quasi-experiment, where each player was their own control based on a control period that lasted for 3 months, and an experimental period that lasted for 5 months. Accordantly, the time each player spent with BEMER therapy was used as a control variable. Multivariate analyses of variance using FFMANOVA and univariate ANOVA with False Discovery Rate adjusted p -values show that physical performance (total distance, distance per minute, sprint meters >22.5 kmh, accelerations and decelerations) significantly peak on game day compared with ordinary training days and days related to game days. The results also show that sleep quantity and quality are significantly reduced on game night, which indicate disturbed sleep caused by the peak in physical load. Most sleep variables significantly increased in the experiment period, where BEMER therapy was used, compared to the control period before the introduction of BEMER therapy. Further, the analyses show that players who spent BEMER therapy >440 h had the most positive effects on their sleep, and that these effects were significantly compared to the players who used BEMER therapy <440 h. The findings are discussed based on the function of sleep and the different sleep stages have on recovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Moen, Pettersen, Gjertsås, Vatn, Ravenhorst, Kvålsvoll, Liland and Mosleth.)

The current study aimed to examine sleep characteristics of esport players and the stipulated effects of game performance on consecutive sleep characteristics using residual dynamic structural equation modeling (RDSEM). A sample of 27 Counterstrike players with a mean age of 18½ years participated in the current study. Sleep was detected over a period of 56 days with a Somnofy sleep monitor that utilizes an impulse radio ultra-wideband puls radar and Dopler technology, and weekly game performance was reported by the players. The results showed that esport players' sleep characteristics were in the lower levels of recommended guidelines and that sleep onset started later and sleep offset ended later in the morning compared with athletes from other traditional sports. The esport players displayed stable patterns in sleep onset, sleep offset, time in bed, sleep efficiency and non-REM respiration rates per minute (NREM RPM). On the between-person level, esport players with better game performance spent more time sleeping ( r = 0.55) and scored lower on NREM RPM ( r = -0.44). Unstandardized within-person cross-lagged paths showed that better game performance predicted subsequent earlier sleep offset. The within-level standardized estimates of the cross-lagged paths revealed that participants with better game performance spent subsequently more time in deep sleep (0.20), less time in light sleep (-0.14), less time in bed (-0.16), and displayed lower NREM RPM (-0.21), earlier sleep offset (-0.21), and onset (-0.09). The findings of better game performance being related to better sleep are discussed in terms of existing knowledge on how stress responses elicitated by poor performance might impact on non-REM respiration rates and sleep., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Moen, Vatn, Olsen, Haugan and Skalicka.)

Background and Aims: The long-term course of ulcerative colitis [UC] is difficult to predict. Mortality, colectomy, cancer, and hospitalisation represent hard outcomes of disease. Moreover, knowledge on the risk of relapses and need for potent medication add important information about living with UC. We aimed to evaluate the course and prognosis of UC during the first 20 years after diagnosis, and to identify early prognostic risk factors., Methods: From 1990 to 1994, a population-based inception cohort of patients with inflammatory bowel disease was enrolled in South-Eastern Norway. A systematic follow-up [FU] was conducted at 1,5, 10, and 20 years after diagnosis. Clinical outcomes were recorded continuously, and possible relationships between early disease characteristics and outcomes were analysed using multiple regression analysis., Results: Among 519 UC patients, 119 died, 60 were lost to FU, and 340 were included in the FU cohort. The 20-year cumulative risk of colectomy was 13.0% (95% confidence interval [CI] [11.4-14.6]). Extensive colitis at diagnosis was independently associated with an increased risk of colectomy compared with proctitis (hazard ratio [HR] = 2].8, 95% CI [1.3-6.1]). In contrast, mucosal healing at 1-year FU was independently associated with reduced risk of colectomy [HR = 0.4, 95% CI [0.2-0.8]), and inversely associated with subsequent risk of relapse [adjusted HR = 0.5, 95% CI [0.3-0.7])., Conclusions: The overall risk of colectomy in our cohort was lower than expected from previous studies, although considerable for patients with extensive colitis at diagnosis. Early mucosal healing was associated with better disease outcomes 20 years after diagnosis., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background and Aims: As inflammatory bowel disease (IBD) becomes more prevalent, the challenges that gastroenterologists face in managing these patients evolve. We aimed to describe the most important challenges facing gastroenterologists from around the world and compare these between those working in developed and developing countries., Methods: An online questionnaire was developed, and a link distributed to gastroenterologists. Data were analyzed descriptively using Friedman and Wilcoxon matched-pair signed rank tests to compare rankings for responses. Mann-Whitney U tests were used to compare rankings between responses from gastroenterologists from developed and developing countries. Lower scores reflected greater challenges., Results: Of 872 who started, 397 gastroenterologists (45.5%) completed the survey. Respondents represented 65 countries (226 [56.9%] from developed countries). Overall, the challenge ranked most important (smallest number) was increasing IBD prevalence (13.6%). There were significant differences in mean ranking scores for many simple aspects of care for those from developing countries compared to providers from developed countries, such as access to simple IBD treatments (5.52 vs. 6.02, p = 0.01), access to anti-TNF drugs including dose escalation (3.33 vs. 3.93, p < 0.01), access to good stoma care (2.57 vs. 3.03, p < 0.001), access to therapeutic drug monitoring (1.47 vs. 1.84, p < 0.001), and access to care for people from low socioeconomic status (2.77 vs. 3.37, p < 0.001)., Conclusions: Increasing IBD prevalence is seen by gastroenterologists as the greatest challenge facing them. There are significant differences between the IBD challenges facing gastroenterologists from developed and developing countries that reflect inequities in access to health care., Competing Interests: R.B.G. − Speaker fees: AbbVie, Janssen, Ferring, and Zespri. Research grants: Zespri, AbbVie, and Pfizer. Advisory board: Zespri, AbbVie, and Janssen. A.M.M. − No disclosures of conflicts of interest. M.V. − Research support: Tillots, Ferring, and Genetic Analysis. Advisory Board: Genetic Analysis. D.T.R. − Research funding: Takeda. Consultant: AbbVie; Abgenomics; Allergan, Inc.; Arena Pharmaceuticals; Biomica; Bristol-Myers Squibb; Dizal Pharmaceuticals; Ferring Pharmaceuticals, Inc.; Genentech/Roche; Janssen Pharmaceuticals; Lilly; Mahana Therapeutics; Medtronic; Merck & Co., Inc.; Napo Pharmaceuticals; Pfizer; Prometheus Laboratories; Shire; Takeda; and Target PharmaSolutions, Inc. F.S. − Consultant, speaker, and grant recipient from Eurofarma, Ferring, Janssen, Pfizer, Takeda, and UCB. E.V.L. − Consultant: AbbVie, Allergan, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Eli Lilly, Genentech, Gilead, Janssen, Pfizer, Takeda, and UCB Biopharma. Research support: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Gilead, Janssen, Pfizer, Takeda, and UCB Biopharma. W.K. − No disclosures or conflicts of interest. C.T. − No disclosures or conflicts of interest. J.-F.C. reports receiving research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc., Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene Corporation, Celltrion, Eli Lilly, Enterome, Ferring Pharmaceuticals, Genentech, Janssen Pharmaceuticals, Landos, Ipsen, Medimmune, Merck, Novartis, Pfizer, Shire, Takeda, Tigenix, and Viela Bio; and hold stock options in Intestinal Biotech Development and Genfit. S.C.N. − Speaker fees: AbbVie, Janssen, Ferring, Takeda, and Tillots. Research grants: AbbVie and Ferring. G.A. − Research grants: AbbVie and MSD. Speaker fees: Janssen, Takeda, Ferring, MSD, and AbbVie. Consultancy fees: AbbVie, MSD, and Takeda. C.N.B. is supported in part by the Bingham Chair in Gastroenterology. He has been on advisory boards for AbbVie Canada, Ferring Canada, Janssen Canada, Shire Canada, Takeda Canada, and Pfizer Canada; consulted to Mylan Pharmaceuticals; has received educational grants from AbbVie Canada, Pfizer Canada, Shire Canada, Takeda Canada, and Janssen Canada; and has been on the speaker's panel for Janssen Canada, Medtronic Canada, Takeda Canada, and Shire Canada., (Copyright © 2021 by S. Karger AG, Basel.)

Background: Crohns disease [CD] is a chronic inflammation in the gut that often progresses to fibrosis. Magnetic resonance enterography [MRE] is an important diagnostic tool in evaluating CD. We aimed to assess the prevalence of inflammation and stricturing disease in patients with long-term CD, and to investigate associations with clinical factors., Methods: We performed a follow-up analysis of a population-based cohort of 237 CD patients in south-eastern Norway 20 years after diagnosis; 95 patients were examined with MRE, and the magnetic enterographic global score [MEGS] was calculated. We assessed inflammation and strictures during the follow-up. Association of the MEGS and bowel strictures with clinical variables was examined by univariate regression analysis., Results: Of the 237 patients, 62 [65.3%] had active inflammation mostly affecting the terminal ileum; 35 [36.8%] had substantial inflammation according to MEGS, which associated with inflammatory biomarkers during the follow-up; and 25 [26.3%] had stricturing disease that associated with age (odds ratio [OR] = 0.92), initial use of systemic steroids [OR = 3.36], and inflammatory biomarkers. Most patients with strictures were treated with surgery without recurrence [n = 24, 42.1%] and seven [21.2%] strictures in the terminal ileum healed without surgery., Conclusions: Twenty years after the diagnosis, the majority of patients had active inflammation, often complicated by stricturing disease. Most patients with strictures were treated with surgery without recurrence, and some strictures resolved over time. Inflammatory biomarkers, extensive and complicated disease type, and use of systemic medication associated with both inflammation and stricturing disease., (Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Peripheral arthritis and related musculoskeletal manifestations, often classified as peripheral spondyloarthritis, are frequently seen in patients with inflammatory bowel disease (IBD). Few long-term studies have reported on the prevalence of these conditions. The aim of this study was to determine the prevalence of IBD-related peripheral arthritis and peripheral spondyloarthritis in IBD patients during 20 years of disease course, and to assess whether these conditions were associated with the intestinal IBD severity and activity., Materials and Methods: In an inception cohort (the IBSEN study), IBD patients were followed prospectively for 20 years. At the 5 year follow-up the patients underwent a rheumatological examination and at the 20 year follow-up they completed a questionnaire with identical questions. When peripheral arthritis was characteristic and not explained by other specific diagnoses, it was defined as IBD-related peripheral arthritis. The Assessment of Spondyloarthritis International Society criteria were used to define peripheral spondyloarthritis, including patients with peripheral arthritis, enthesitis and/or dactylitis., Results: After 20 years of follow-up, 441 patients were included (296 ulcerative colitis and 145 Crohn's disease). The prevalence of IBD-related peripheral arthritis was 17.2% and peripheral spondyloarthritis 27.9% during the disease course. IBD severity and activity were not different between those with a history of IBD-related peripheral arthritis or peripheral spondyloarthritis and those without. A higher proportion of women had IBD-related peripheral arthritis and peripheral spondyloarthritis., Conclusion: During 20 years of disease course, more than every sixth patient had suffered from IBD-related peripheral arthritis and every fourth from peripheral spondyloarthritis.

Aim: To evaluate the use of chromoendoscopy for surveillance of ulcerative colitis in a real-life community hospital setting., Methods: Patients with extensive ulcerative colitis, having disease duration of more than 8 years and who presented between the years of 1999 to 2013, were offered enrolment in this single cohort prospective study. All participants underwent standard bowel preparation with sodium phosphate and chromoendoscopy. Two expert endoscopists, novice to chromoendoscopy, evaluated each segment of the colon with standard-definition colonoscopes after spray application of 0.4% indigo carmine. All observed lesions were recorded and evaluated before being removed and/or biopsied. In addition, nontargeted biopsies were taken from each segment of the colon. The dysplasia detection rate and dysplasia detection yield were ascertained., Results: A total of 21 neoplastic lesions (2 carcinomas, 4 of high-grade dysplasia and 15 of low-grade dysplasia) and 27 nondysplastic lesions were detected in 16 of the total 67 patients (70% male; median disease duration: 17 years; median age at diagnosis: 25 years; 92% aminosalicylate-treated). The dysplasia detection rate was 10.5% (7/67 patients). The dysplasia detection yield was 20.8% (10/48) for targeted biopsies and 3.5% (11/318) for nontargeted biopsies. The sensitivity and specificity for the macroscopic evaluation of neoplasia using chromoendoscopy were 48% [95% confidence interval (CI): 26%-70%] and 96% (95%CI: 93%-98%), respectively. The positive predictive and negative predictive values were 42% (95%CI: 27%-59%) and 97% (95%CI: 95%-98%), respectively. A total of 19/21 dysplastic lesions were detected in mucosa with histologic inflammation., Conclusion: Chromoendoscopy seems to be of value for dysplasia surveillance of ulcerative colitis in a community hospital setting. The yield of non-targeted biopsies is negligible., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest.

Background: The long-term effects of sigmoidoscopy screening on colorectal cancer (CRC) incidence and mortality in women and men are unclear., Objective: To determine the effectiveness of flexible sigmoidoscopy screening after 15 years of follow-up in women and men., Design: Randomized controlled trial. (ClinicalTrials.gov: NCT00119912)., Setting: Oslo and Telemark County, Norway., Participants: Adults aged 50 to 64 years at baseline without prior CRC., Intervention: Screening (between 1999 and 2001) with flexible sigmoidoscopy with and without additional fecal blood testing versus no screening. Participants with positive screening results were offered colonoscopy., Measurements: Age-adjusted CRC incidence and mortality stratified by sex., Results: Of 98 678 persons, 20 552 were randomly assigned to screening and 78 126 to no screening. Adherence rates were 64.7% in women and 61.4% in men. Median follow-up was 14.8 years. The absolute risks for CRC in women were 1.86% in the screening group and 2.05% in the control group (risk difference, -0.19 percentage point [95% CI, -0.49 to 0.11 percentage point]; HR, 0.92 [CI, 0.79 to 1.07]). In men, the corresponding risks were 1.72% and 2.50%, respectively (risk difference, -0.78 percentage point [CI, -1.08 to -0.48 percentage points]; hazard ratio [HR], 0.66 [CI, 0.57 to 0.78]) (P for heterogeneity = 0.004). The absolute risks for death from CRC in women were 0.60% in the screening group and 0.59% in the control group (risk difference, 0.01 percentage point [CI, -0.16 to 0.18 percentage point]; HR, 1.01 [CI, 0.77 to 1.33]). The corresponding risks for death from CRC in men were 0.49% and 0.81%, respectively (risk difference, -0.33 percentage point [CI, -0.49 to -0.16 percentage point]; HR, 0.63 [CI, 0.47 to 0.83]) (P for heterogeneity = 0.014)., Limitation: Follow-up through national registries., Conclusion: Offering sigmoidoscopy screening in Norway reduced CRC incidence and mortality in men but had little or no effect in women., Primary Funding Source: Norwegian government and Norwegian Cancer Society.

Background & Aims: Magnetic resonance enterography (MRE) is used to evaluate the extent and complications of Crohn's disease (CD). MRE results are used in calculation of the Lémann index (LI) score, which quantifies bowel damage. The long-term outcomes of CD are uncertain; we aimed to assess bowel disease and damage in patients with CD for 20 years using MRE and the LI., Methods: We performed a follow-up analysis of a population-based cohort of 237 patients in southeastern Norway diagnosed with CD from 1990 to 1993. Twenty years after diagnosis, 156 attended the evaluation in which they were offered routine clinical blood tests and colonoscopies. Ninety-six patients were examined by MRE and LI scores were calculated. The independent association of the LI score with clinical variables was examined by univariate analysis., Results: Sixty-five patients (67.7%) had CD manifestations based on findings from MRE (36.9%), colonoscopy (29.2%), or both (33.9%). MRE findings changed disease classification for 8 patients (8.3%). The median LI score was 4.6 (interquartile range, 17.5) and associated with younger age (P = .02), complicated ileocolonic phenotype (P < .001), and use of biologic (P < .001), or immunosuppressant therapies (P = .045). Factors independently associated with LI score during the follow-up period were age, complicated disease, use of medication, and markers of inflammation., Conclusions: In a population-based study of 237 patients with CD in Norway, we found that almost 68% had imaging features of CD, half of which were only detectable by MRE. LI score associated with ongoing active disease. Young age, complicated disease, and persistent inflammation were associated with bowel damage., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We aimed to identify novel protein biomarkers of disease severity and prognosis in primary sclerosing cholangitis (PSC)., Methods: Using a bead-based array targeting 63 proteins, we profiled a derivation panel of Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls) and a Finnish validation panel (34 PSC, 10 disease controls). Selected identified proteins were measured in serum from two Norwegian PSC cohorts (n=167 [1992-2006] and n=138 [2008-2012]), inflammatory bowel disease (n=96) and healthy controls (n=100)., Results: In the bile derivation panel, the levels of 14 proteins were different between PSC patients and controls (p<0.05); all were confirmed in the validation panel. Twenty-four proteins in the bile derivation panel were significantly (p<0.05) different between PSC patients with mild compared to severe cholangiographic changes (modified Amsterdam criteria); this was replicated for 18 proteins in the validation panel. Interleukin (IL)-8, matrix metallopeptidase (MMP)9/lipocalin (LCN)2-complex, S100A8/9, S100A12 and tryptophan hydroxylase (TPH)2 in the bile were associated with both a PSC diagnosis and grade of cholangiographic changes. Stratifying PSC patients according to tertiles of serum IL-8, but not MMP9/LCN2 and S100A12, provided excellent discrimination for transplant-free survival both in the serum derivation and validation cohort. Furthermore, IL-8 was associated with transplant-free survival in multivariable analyses in both serum panels independently of age and disease duration, indicating an independent influence on PSC progression. However, the Enhanced Liver Fibrosis (ELF®) test and Mayo risk score proved to be stronger predictors of transplant-free survival., Conclusions: Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC., Lay Summary: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We have identified inflammatory proteins including calprotectin and IL-8 as important indicators of disease severity and prognosis in bile and serum from patients with primary sclerosing cholangitis., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: The prevalence of primary sclerosing cholangitis (PSC) among patients with inflammatory bowel disease (IBD) is unclear. Patients with IBD might be screened for PSC using magnetic resonance cholangiography (MRC). We aimed to estimate the frequency and distribution of MRC-detected lesions that indicate PSC in patients with IBD 20 years after their initial diagnosis and to identify clinical characteristics associated with these findings., Methods: We performed a follow-up analysis of a population-based cohort of 756 patients in South-Eastern Norway diagnosed with IBD from January 1, 1990 through December 31, 1993. Of these subjects, 470 attended a follow-up evaluation 20 years later in which they were offered routine clinical blood testing and ileocolonoscopy; 322 were screened by MRC (222 with ulcerative colitis and 100 with Crohn's disease). Two radiologists independently evaluated results from the MRC examinations., Results: In the MRC examination, 24 patients (7.5%) were found to have PSC-like lesions; only 7 of these patients (2.2%) were known to have PSC. One patient was initially missed and 1 had small-duct PSC, so the final prevalence of PSC was 8.1%. Extensive colitis, a high prevalence of colectomy, and chronic and continuous symptoms of IBD occurred in significantly more patients with suspected PSC than without PSC (P = .029, P = .002, and P = .012, respectively). Among patients with subclinical features of PSC, the MRC progression score for PSC increased when they were re-examined after a median 3.2 years (P = .046)., Conclusions: Using MRC analysis of patients with long-term IBD, we found the prevalence of PSC to be around 3-fold higher than that detected based on symptoms. Sixty-five percent of patients had subclinical PSC associated with progressive IBD, with no biochemical abnormalities and mild disease, based on radiology findings. PSC appears to progress in patients with subclinical disease, but long-term outcomes are not known., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: There is a need to determine biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC). We evaluated the prognostic utility of the enhanced liver fibrosis (ELF) score in Norwegian PSC patients. Serum samples were available from 305 well-characterized large-duct PSC patients, 96 ulcerative colitis patients, and 100 healthy controls. The PSC patients constituted a derivation panel (recruited 1992-2006 [n = 167]; median age 41 years, 74% male) and a validation panel (recruited 2008-2012 [n = 138]; median age 40 years, 78% male). We used commercial kits to analyze serum levels of hyaluronic acid, tissue inhibitor of metalloproteinases-1, and propeptide of type III procollagen and calculated ELF scores by the previously published algorithm. Results were also validated by analysis of ELF tests using the ADVIA Centaur XP system and its commercially available reagents. We found that PSC patients stratified by ELF score tertiles exhibited significantly different transplant-free survival in both panels (P < 0.001), with higher scores associated with shorter survival, which was confirmed in the validation panel stratified by ELF test tertiles (P = 0.003). The ELF test distinguished between mild and severe disease defined by clinical outcome (transplantation or death) with an area under the curve of 0.81 (95% confidence interval [CI] 0.73-0.87) and optimal cutoff of 10.6 (sensitivity 70.2%, specificity 79.1%). In multivariate Cox regression analysis in both panels, ELF score (hazard ratio = 1.9, 95% CI 1.4-2.5, and 1.5, 95% CI 1.1-2.1, respectively) was associated with transplant-free survival independently of the Mayo risk score (hazard ratio = 1.3, 95% CI 1.1-1.6, and 1.6, 95% CI 1.2-2.1, respectively). The ELF test correlated with ultrasound elastography in separate assessments., Conclusion: The ELF score is a potent prognostic marker in PSC, independent of the Mayo risk score., (© 2015 by the American Association for the Study of Liver Diseases.)

Objectives: Pancreatic neuroendocrine tumors (P-NETs) account for 2-3% of all pancreatic neoplasms. The aim of our study was to investigate survival and prognostic factors in patients with P-NETs., Material and Methods: We retrospectively reviewed the medical records of 114 patients diagnosed with well-differentiated P-NETs from 1982 through 2010. We studied demographical, clinical, radiological, and histopathological characteristics., Results: Median age at diagnosis was 57 years (range 32-83); 53% were men and 78% had nonfunctional tumors. The most common presenting symptoms were abdominal pain (41%), weight loss (36%), and diarrhea (25%); 19% of the tumors were incidental findings. Median duration of symptoms before diagnosis was 4 months, 3 months for nonfunctional, and 12 months for functional tumors (p < 0.001). At diagnosis, 32.5% patients had local, 22.8% had regional, and 44.7% had distant disease. Men had more often distant disease at diagnosis (p = 0.02). Median survival was 6.6 years (95% confidence interval [CI]: 4.0-9.2). Overall 5-year survival was 53.9% (95% CI: 43.4-63.3). For those with local disease and those with distant disease at diagnosis, the 5-year survivals were 70.2% (95% CI: 49.9-83.6) and 33.0% (95% CI: 19.7-46.7), respectively. Surgery with curative intent was performed on 46 patients. Newly detected liver metastases were diagnosed up to 10 years after surgery in this group. In patients with metastases, palliative surgery (debulking) did not have a significant effect on survival compared to those who had no surgery., Conclusion: Distant metastases, Ki-67 > 2%, nonfunctional tumors, elevated level of chromogranin A, and palliative treatment were associated with poor survival.

Unlabelled: Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P = 3.0 × 10(-9) in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 × 10(-8) , OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor., Conclusion: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Corticosteroids are the mainstay of therapy for severe ulcerative colitis. However, at least a third of patients fail to respond and face a colectomy. In these, rescue therapy with cyclosporine or infliximab (IFX), aimed at avoiding surgery, has been used in recent years. Of the two options, infliximab is largely preferred in both Sweden and Norway, whereas cyclosporine (CyA) is generally regarded as difficult to use, rather toxic and showing limited long-term efficacy. In light of some new recent data, herein, we provide an update of the literature in the field. It appears that there are theoretical and practical arguments on each side, and as of today, the choice between IFX or CyA for rescue therapy cannot be made on strong evidence. Thus, the best choice of medical rescue therapy will depend on the results of ongoing RCTs as well as future research in the field.

Objective: Interleukin (IL)-33 is a nuclear protein that is released from stressed or damaged cells to act as an alarmin. We investigated the effects of IL-33 on endothelial cells, using the prototype IL-1 family member, IL-1β, as a reference., Methods and Results: Human umbilical vein endothelial cells were stimulated with IL-33 or IL-1β, showing highly similar phosphorylation of signaling molecules, induction of adhesion molecules, and transcription profiles. However, intradermally injected IL-33 elicited significantly less proinflammatory endothelial activation when compared with IL-1β and led us to observe that quiescent endothelial cells (ppRb(low)p27(high)) were strikingly resistant to IL-33. Accordingly, the IL-33 receptor was preferentially expressed in nonquiescent cells of low-density cultures, corresponding to selective induction of adhesion molecules and chemokines. Multiparameter phosphoflow cytometry confirmed that signaling driven by IL-33 was stronger in nonquiescent cells. Manipulation of nuclear IL-33 expression by siRNA or adenoviral transduction revealed no functional link between nuclear, endogenous IL-33, and exogenous IL-33 responsiveness., Conclusions: In contrast to other inflammatory cytokines, IL-33 selectively targets nonquiescent endothelial cells. By this novel concept, quiescent cells may remain nonresponsive to a proinflammatory stimulus that concomitantly triggers a powerful response in cells that have been released from contact inhibition.

Neuroendocrine tumors (NETs) arising in the small intestine are known to produce vasoactive substances, including serotonin, that may result in the carcinoid syndrome (flushing, diarrhea, bronchoconstriction, and carcinoid heart disease). Measurement of the serotonin breakdown product 5-hydroxyindoleacetic acid (5-HIAA) in urine is important in diagnosing and monitoring of patients with intestinal NETs. Our aim was to compare 5-HIAA measurement in 24-h urine sampling with overnight (∼8-h) sampling in patients with known NETs, or at follow-up of patients potentially cured for their NETs. Twenty-four-hour and overnight urine samples were collected from 34 patients and analyzed for urinary 5-HIAA (U5-HIAA) using HPLC. Comparison of the overnight sampling values with the 24-h values showed no difference, P=0.45, and there was a significant direct correlation between the two samples using linear regression (R=0.97, P<0.001). U5-HIAA sample collection during a nightly interval of ∼8 h appears to have the same accuracy as the 24-h collection in this group of patients.

Background: Inflammatory bowel disease (IBD) of pediatric and adult onset differs in several aspects although little knowledge exists about pathogenic disparity. Regulatory T cells (Tregs) characterized as CD4+CD25+Foxp3+ are modulators of gut homeostasis, but their role in human IBD remains unclear., Objective: To evaluate the mucosal distribution of Foxp3+ and CD25+ cells in untreated pediatric IBD patients at the time of diagnosis., Material and Methods: Untreated pediatric (n = 14) and adult (n = 12) Crohn's disease (CD) patients were prospectively included together with age-matched symptomatic controls. Colonic and ileal mucosal biopsies collected at diagnosis were studied by immunohistochemistry for enumeration of T cells and for mucosal expression of Foxp3 and CD25. Multicolor immunofluorescence staining was performed in situ to phenotype Foxp3+ cells as Tregs and characterize the CD25+ cells., Results: The density of mucosal T cells displayed only small variations, while that of Foxp3+ cells and CD25+ cells was increased in CD patients. Multicolor immunofluorescence showed that most CD25+ cells were macrophages. Interestingly, in the ileum of pediatric CD patients the density of Foxp3+ cells was significantly higher than in adult CD patients. Co-expression of Foxp3 and CD25, as well as Foxp3 and CTLA-4, indicated that the Foxp3+ cells were Tregs., Conclusion: Mucosal numbers of Foxp3(+) Tregs and activated (CD25+) macrophages are elevated in both pediatric and adult ileal CD. The greater increase of ileal Foxp3+ Tregs in pediatric CD than in adult CD might contribute to the relatively less frequent phenotype of isolated ileal enteritis in CD children.

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Background/aims: Carcinoid heart disease (CHD), a complication of neuroendocrine tumors (NETs), is characterized by right heart fibrotic lesions. Though serotonin is likely involved, the pathogenesis of CHD remains unclear. Cytokines and growth factors with fibrogenic properties may play a role. We sought to examine the relationship between plasma levels of fibrogenic cytokines and growth factors and CHD, both to provide further insight into possible biomarkers of CHD as well as into the possible pathogenesis of CHD., Methods: Plasma samples obtained from 71 patients with NETs and 18 controls were analyzed using enzyme immunoassays. All patients underwent echocardiography., Results: 15 patients (21%) had CHD, all of whom had carcinoid syndrome compared to 82% of those without CHD. CHD patients were older (p = 0.01), had larger (p = 0.007) and more numerous liver metastases (p = 0.04), and had elevated 24-hour urinary 5-hydroxyindoleacetic acid (U-5HIAA) (p = 0.03) and serum chromogranin A levels (p = 0.02). CHD patients had higher plasma levels of C-reactive protein (p = 0.03), osteoprotegerin (p = 0.005), and activin A (p = 0.005) than patients without CHD. A significant direct correlation between activin A and U-5HIAA levels was observed in the total patient group (r = 0.30, p = 0.02). Activin A ≥0.34 ng/ml (odds ratio (OR) 5.35 [1.01; 28.17], p = 0.048) and age ≥69.5 (OR 6.10 [1.60; 23.24], p = 0.008) were independent predictors of CHD. Activin A levels were elevated to the same degree in both early and advanced CHD. Activin A ≥0.34 ng/ml had 87% sensitivity and 57% specificity for detecting CHD (p = 0.006)., Conclusion: Elevated plasma activin A levels are associated with the presence of CHD., (Copyright © 2010 S. Karger AG, Basel.)

Aims: Proteobacteria are widespread on earth. Recently, it has been discovered that a diverse repertoire of proteobacteria are also dominant in tap water. It is therefore important to use high-throughput monitoring tools for tap water. Here, the high-throughput assay ProteoQuant was developed to quantify the main proteobacterial phyla in tap water., Methods and Results: The principle of ProteoQuant is proteobacterial-selective 23S rRNA gene PCR amplification, with multiple competitive TaqMan probes for quantifying the phyla Alpha-, Beta- and Gamma-proteobacteria. The ProteoQuant assay was evaluated, analysing both designed proteobacterial mixes and rRNA gene clone libraries from tap water. These evaluations showed a good coverage and accuracy of the ProteoQuant assay., Conclusions: Large-scale tap water screening using ProteoQuant revealed a dominance of Beta-proteobacteria and a potential interaction between Alpha- and Beta-proteobacteria. Gamma-proteobacteria, on the other hand, seemed independent of the two other phyla., Significance and Impact of the Study: The ProteoQuant assay will potentially be important for future understanding of the ecological forces shaping the tap water microbiota.

We analyzed the temporal and spatial diversity of the microbiota in a low-usage and a high-usage hospital tap. We identified a tap-specific colonization pattern, with potential human pathogens being overrepresented in the low-usage tap. We propose that founder effects and local adaptation caused the tap-specific colonization patterns. Our conclusion is that tap-specific colonization represents a potential challenge for water safety.

Objective: Small intestinal neuroendocrine tumors (SI-NETs) make up 38% of gastroenteropancreatic neuroendocrine tumors. We report our experience with SI-NETs at the National Center for Neuroendocrine Tumors in Norway, focusing on prognostic factors and survival., Material and Methods: The medical records of 258 patients with SI-NETs diagnosed between 1983 and 2007 were retrospectively reviewed. Demographic, clinical and tumor characteristics were registered in a database., Results: Median age at diagnosis was 62 years (range 28-84); 53% of patients were men. Median survival was 9.3 years [95% confidence interval (CI) 7.6; 10.8]. Survival did not improve for patients diagnosed between 1998 and 2007 compared with those diagnosed between 1990 and 1997 (p=0.44), median survival 8.1 [7.1;9.1] versus 6.8 [4.0; 9.5] years. Overall 5-year survival was 72%, while expected 5-year survival in the general population was 92%. The corresponding relative 5-year survival for the patient group was 78%. Distant metastases, urinary 5-hydroxyindoleacetic acid ratio > or =3.7 times the upper limit of normal, chromogranin A ratio > or =6.2 times the upper limit of normal, age > or =64, male gender, carcinoid heart disease, and Ki-67 > or =5% were associated with decreased survival. Using multivariate analysis, only distant metastases (hazard ratio (HR) 1.98 [1.04;3.76], p=0.04), chromogranin A ratio > or =6.2 (HR 1.90 [1.12; 3.20], p=0.02), and age > or =64 (3.12 [1.93; 5.04], p<0.001) remained independent predictors., Conclusions: Survival did not improve over the study period. Overall and relative 5-year survival compared favorably with that in population-based studies. Distant metastases, elevated chromogranin A levels, and advanced age were the only independent predictors of poor survival.