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BACKGROUND: Bile acid diarrhoea is a common but overlooked cause of chronic watery diarrhoea. Plasma 7α-hydroxy-4-cholesten-3-one (C4) is an alternative to the gold standard tauroselcholic [75Se] acid (SeHCAT) test. Low-certainty evidence supports sequestrant treatment, including colesevelam. We aimed to determine the efficacy and safety of colesevelam in bile acid diarrhoea.METHODS: In this randomised, double-blind, placebo-controlled, investigator-initiated phase 4 trial of the sequestrant colesevelam in bile acid diarrhoea (SINBAD), we enrolled consecutive patients aged 18-79 years without inflammatory bowel disease attending SeHCAT testing for suspected bile acid diarrhoea at four Danish secondary care centres. Participants were randomly allocated 1:1 to receive 12 days of treatment with colesevelam (overencapsulated tablets of 625 mg) or placebo, with the starting dose of two capsules twice daily and titrated to effect during the first 5 days of treatment. A pharmacist independent of the clinical investigators generated a randomisation list on the web page randomization.com using block randomisation (randomisation was not stratified). C4 and SeHCAT diagnostic results were blinded during treatment. We treated all patients with diarrhoea, with a daily mean of 3·0 or more bowel movements or 1·0 or more watery bowel movements (Bristol stool scale type 6 and 7). Remission was defined as the absence of both these criteria during treatment days 6-12. The primary outcome was the intention-to-treat remission rate in bile acid diarrhoea diagnosed by C4 concentration greater than 46 ng/mL. A secondary outcome was the intention-to-treat remission rate in bile acid diarrhoea diagnosed by SeHCAT retention of 10% or less. This trial is registered with ClinicalTrials.gov, NCT03876717.FINDINGS: Between Oct 25, 2018, and July 1, 2021, 168 patients were randomly assigned to receive colesevelam (n=84) or placebo (n=84). 41 patients had C4 concentration greater than 46 ng/mL (22 assigned to the colesevelam group and 19 to the placebo group). For the C4-defined primary outcome, 14 (64%) of 22 participants receiving colesevelam versus three (16%) of 19 participants receiving placebo achieved remission (adjusted odds ratio 9·1, 95% CI 1·9-62·8; p=0·011). For the SeHCAT-defined secondary outcome, 75 of the 168 participants had retention of less than 10% (37 assigned to the colesevelam group and 38 assigned to the placebo group); 22 (59%) of 37 participants receiving colesevelam achieved remission versus five (13%) of 38 participants receiving placebo (adjusted odds ratio 11·1, 95% CI 3·4-45·6; p=0·00020). There were no serious adverse events. Common adverse events were transient. For patients receiving colesevelam within the primary outcome population, five had abdominal pain, nine had bloating, and four had nausea. For patients receiving placebo, four had abdominal pain, four had bloating, and one had nausea. No participants with bile acid diarrhoea withdrew due to adverse events.INTERPRETATION: Colesevelam was superior to placebo at inducing remission of bile acid diarrhoea diagnosed with C4 concentration greater than 46 ng/mL. Secondary outcome data suggest similar efficacy treating SeHCAT-defined bile acid diarrhoea. Colesevelam was safe during the treatment.FUNDING: Fabrikant Vilhelm Pedersen og hustrus mindelegat; recommended by the Novo Nordisk Foundation.

BackgroundThe pathophysiological mechanisms of bile acid diarrhoea after cholecystectomy are unknown. Therefore, we aimed to explore the effects of cholecystectomy on the plasma biomarkers of bile acid diarrhoea: fibroblast growth factor 19 and 7α-hydroxy-4-cholesten-3-one.MethodsPatients were examined prospectively before and after cholecystectomy. Diary registration of bowel habits with the Bristol stool scale was done for 7 days before each visit. Blood was collected at fasting and after ingestion of a solid study meal with 1250 mg unconjugated chenodeoxycholic acid. Plasma fibroblast growth factor 19 was measured with enzyme-linked immunosorbent assay and the complete bile acid profile including 7α-hydroxy-4-cholesten-3-one with high-performance liquid chromatography–tandem mass spectrometry.ResultsEighteen patients completed the study. The median postoperative follow-up time was 4.6 months (interquartile range [IQR] 3.9-5.8). Diary-registered bowel movement frequency and stool consistency were unchanged; none developed diarrhoea. Before cholecystectomy, mean fibroblast growth factor 19 was 102 pg/mL (95% CI 74-141) vs 92 pg/mL (67-125) after (P = .29; paired t test). Following the meal, the median 150-minute increment from fasting in fibroblast growth factor 19 was 81 pg/mL (IQR: −20 to 274) before and 186 pg/mL (111-382) after cholecystectomy (P = .03; Wilcoxon-test). Mean fasting 7α-hydroxy-4-cholesten-3-one was unchanged 6.0 ng/mL (4.1-8.7) vs 7.5 ng/mL (5.5-10.0) (P = .63; paired t test).ConclusionsThe stimulated postprandial response in fibroblast growth factor 19 increased after cholecystectomy, whereas fasting plasma biomarkers and bowel habits did not change significantly 3-6 months after cholecystectomy. ClinicalTrials.gov: NCT03168555.

Background and aims: Incomplete microscopic colitis (MCi) is a subtype of microscopic colitis (MC). Budesonide is recommended as a first-line treatment for MC. However, randomised trials on efficacy of treatment in MCi are missing. We therefore performed a randomised, placebo-controlled trial to evaluate budesonide as induction therapy for MCi. Methods: Patients with active MCi were randomly assigned to either budesonide 9 mg once daily or placebo for 8 weeks in a double-blind, double-dummy design. The primary endpoint was clinical remission, defined as a mean of

Background Microscopic colitis (MC) is a common cause of chronic watery diarrhea. Biopsies with characteristic histological features are crucial for establishing the diagnosis. The two main subtypes are collagenous colitis (CC) and lymphocytic colitis (LC) but incomplete forms exist. The disease course remains unpredictable varying from spontaneous remission to a relapsing course. Aim To identify possible histological predictors of course of disease. Methods Sixty patients from the European prospective MC registry (PRO-MC Collaboration) were included. Digitised histological slides stained with CD3 and Van Gieson were available for all patients. Total cell density and proportion of CD3 positive lymphocytes in lamina propria and surface epithelium were estimated by automated image analysis, and measurement of the subepithelial collagenous band was performed. Histopathological features were correlated to the number of daily stools and daily watery stools at time of endoscopy and at baseline as well as the clinical disease course (quiescent, achieved remission after treatment, relapsing or chronic active) at 1-year follow-up. Results Neither total cell density in lamina propria, proportion of CD3 positive lymphocytes in lamina propria or surface epithelium, or thickness of collagenous band showed significant correlation to the number of daily stools or daily watery stools at any point of time. None of the assessed histological parameters at initial diagnosis were able to predict clinical disease course at 1-year follow-up. Conclusions Our data indicate that the evaluated histological parameters were neither markers of disease activity at the time of diagnosis nor predictors of disease course.

PURPOSE: The diagnosis microscopic colitis (MC) consisting of collagenous colitis (CC) and lymphocytic colitis (LC) relies on histological assessment of mucosal biopsies from the colon. The optimal biopsy strategy for reliable diagnosis of MC is controversial. The aim of this study was to evaluate the distribution of histopathological features of MC throughout the colon.METHODS: Mucosal biopsies from multiple colonic segments of patients with MC who participated in one of the three prospective European multicenter trials were analyzed. Histological slides were stained with hematoxylin-and-eosin, a connective tissue stain, and CD3 in selected cases.RESULTS: In total, 255 patients were included, 199 and 56 patients with CC and LC, respectively. Both groups exhibited a gradient with more pronounced inflammation in the lamina propria in the proximal colon compared with the distal colon. Similarly, the thickness of the subepithelial collagenous band in CC showed a gradient with higher values in the proximal colon. The mean number of intraepithelial lymphocytes was > 20 in all colonic segments in patients within both subgroups. Biopsies from 86 to 94% of individual segments were diagnostic, rectum excluded. Biopsies from non-diagnostic segments often showed features of another subgroup of MC.CONCLUSION: Conclusively, although the severity of the histological changes in MC differed in the colonic mucosa, the minimum criteria required for the diagnosis were present in the random biopsies from the majority of segments. Thus, our findings show MC to be a pancolitis, rectum excluded, questioning previously proclaimed patchiness throughout the colon.

Summary The diagnosis of microscopic colitis (MC) relies on specific histopathological findings in colon biopsies. The number of biopsies needed to diagnose MC remains disputed. The aim of the study was to determine the number and site of biopsies necessary for the diagnosis and the effect of perpendicular orientation when embedding the biopsies. This retrospective multicenter European study included 42 patients with a consensus diagnosis of collagenous colitis (CC), 51 patients with lymphocytic colitis (LC), and three patients with incomplete LC (LCi). The number of individual diagnostic biopsies from each patient was determined. The diagnostic rate of 744 individual biopsies from 96 patients with MC was 69.5% for the specific MC subgroup, 79.4% for MC and 93.4% for MC plus incomplete MC (MCi). The risk of missing a diagnosis of the specific subgroup of MC when analyzing four biopsies was 0.87%, decreasing to 0.18% for MC and 0.0019% for MC plus MCi. More biopsies from the right colon were diagnostic of the specific MC subgroup (76.3% vs. 64.0%, p = 0.0014). Perpendicular orientation of biopsies increased the diagnostic rate of the specific MC subgroup (73.1% vs. 65.0%, p = 0.0201). Histological changes diagnostic of MC were present in almost all biopsies from the right colon, with orientated biopsies more often being diagnostic of the specific MC subgroup. The results of this study indicate that four biopsies from the colon, rectum excluded, are sufficient to diagnose MC.

Background and Aims Patient-reported outcome measures [PROMs] aim to measure patients’ perception of how their disorder influences everyday functioning. The objective of this study was to develop a PROM to assess disease activity in microscopic colitis [MC] fulfilling the requirements of the Food and Drug Administration [FDA]. Methods The European Microscopic Colitis Activity Index [E-MCAI] was developed in four steps. [1] A list of symptoms associated with active MC was created by a group of experts in the field. [2] Content validity of the symptoms was performed by experts [n = 14] and patients [n = 79] using the Content Validity Index. [3] Questions and response alternatives were created for each symptom, and validity of the E-MCAI was evaluated with cognitive interviews with patients [n = 7] and by the experts. [4] A pilot postal survey was performed to ensure usability. Results Seven of the symptoms related to active MC fulfilled the criteria for content validity and were included in the E-MCAI: stool consistency, stool frequency, stools at night, feel a need to pass more stools shortly after a bowel movement, urgent need to empty the bowel, leakage of stool and abdominal pain. The development and validation process resulted in the current version of the E-MCAI consisting of six questions related to MC. Conclusions The E-MCAI was developed using the methods advocated by the FDA. The evaluation indicates good content validity. Further evaluation will be performed to achieve construct validity, reliability and responsiveness in future cross-sectional and longitudinal studies.

Lymphocytic colitis (LC) and LC incomplete (LCi) are common causes of chronic watery diarrhea. The diagnosis relies on clinical findings and histopathologic evaluation. The diagnostic criteria of LC are based on hematoxylin and eosin (HE) staining. However, supplementary immunohistochemical staining for highlighting the lymphocytes in borderline cases is now widely used. This change in diagnostics could lead to incorrectly diagnosing patients with LC and LCi if the present histologic criteria are used. The number of intraepithelial lymphocytes (IELs) was estimated and categorized in intervals based on HE- versus CD3-stained slides from patients with an HE diagnosis of normal colonic mucosa (n = 19), mucosa with nonspecific reactive changes (n = 24), LCi (n = 24), and LC (n = 40). The number of IELs was compared with clinical symptoms. Overall, the number of IELs was higher with CD3 stain compared with HE stain in 73% of cases, unchanged in 26% of cases, and lower in 1 case. The number of IELs detected was higher using the CD3 stain in 53%, 79%, 79%, and 75% of cases included as normal colonic mucosa, nonspecific reactive changes, LCi, and LC, respectively. Based on CD3 stain, 58% of the cases with nonspecific reactive changes fulfilled the HE criteria for LCi, and 79% of the cases with LCi fulfilled the HE criteria for LC. Automated image analysis of CD3-stained slides resulted in even higher numbers of IELs in all 4 diagnostic groups. Conclusively, our data support considering increased cutoff values for LCi and LC when assessed in CD3-stained specimens.

This case report describes a patient with colonic Crohn's disease and perianal disease. The patient experienced extensive and severe pyoderma gangrenosum after colectomy. Steroids and anti-inflammatory medication had no effect on pyoderma or the persistent perianal and rectal disease. All pyoderma lesions eventually healed after proctectomy and excision of perianal fistulae. The relevance and effect of surgically induced remission on medically resistant inflammatory bowel disease-associated pyoderma gangrenosum is highlighted.

Background and Aims The disease course of microscopic colitis [MC] is considered chronic but benign. However, this assumption is based on mainly retrospective studies, reporting on incomplete follow-up of selective cohorts. Systematic, prospective and unbiased data to inform patients and healthcare professionals on the expected course of the disease and real-life response to therapy are warranted. Methods A prospective, pan-European, multi-centre, web-based registry was established. Incident cases of MC were included. Data on patient characteristics, symptoms, treatment and quality of life were systematically registered at baseline and during real-time follow-up. Four disease course phenotypes were discriminated and described. Results Among 381 cases with complete 1-year follow-up, 49% had a chronic active or relapsing disease course, 40% achieved sustained remission after treatment and 11% had a quiescent course. In general, symptoms and quality of life improved after 3 months of follow-up. A relapsing or chronic active disease course was associated with significantly more symptoms and impaired quality of life after 1 year. Conclusions A minority of MC patients follow a quiescent disease course with spontaneous clinical improvement, whereas the majority suffer a chronic active or relapsing disease course during the first year after diagnosis, with persisting symptoms accompanied by a significantly impaired quality of life.

INTRODUCTION: The diagnosis of bile acid diarrhea is often missed because the availability of the seleno-taurohomocholic acid (SeHCAT) test is limited. We aimed to compare the biomarkers 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19) with the SeHCAT test.METHODS: Patients with chronic diarrhea without intestinal resection referred for SeHCAT were prospectively recruited for this diagnostic accuracy study. Blood was sampled at fasting and after a stimulation meal with chenodeoxycholic acid. SeHCAT retention ≤10% defined bile acid diarrhea and >10% defined miscellaneous diarrhea. Receiver operating characteristics (ROC) were analyzed with SeHCAT as the gold standard. www.clinicaltrials.gov (NCT03059537).RESULTS: Patients with bile acid diarrhea (n = 26) had mean C4 of 30 ng/mL (95% confidence interval: 19-46) vs 8 (7-11; P < 0.001) in the miscellaneous diarrhea group (n = 45). Area under the ROC curve (ROCAUC) for C4 was 0.83 (0.72-0.93). C4 < 15 ng/mL had 85% (74%-96%) negative predictive value; C4 > 48 ng/mL had 82% (59%-100%) positive predictive value. Twenty patients had C4 values 15-48 ng/mL, of whom 11/20 had SeHCAT ≤10%. Median fasting FGF19 was 72 pg/mL (interquartile range: 53-146) vs 119 (84-240) (P = 0.004); ROCAUC was 0.71 (0.58-0.83). Stimulated FGF19 responses did not differ (P = 0.54).DISCUSSION: We identified C4 thresholds with clinically useful predictive values for the diagnosis of and screening for bile acid diarrhea in patients with chronic watery diarrhea. Further validation of the cutoff values with the placebo-controlled effect of sequestrant therapy is warranted (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/AJG/B603).

Forward-focused molecular genetics is successfully framing DNA diversity and mapping primary gene functions. However, abandoning the classic Linnaean fingerprint link between the phenome and genome by suppressing gene interaction (pleiotropy), has resulted in a genome-to-phenome gap and poor utilization of molecular data. We demonstrate how to bridge this gap by using an example of a barley mutant seed model, where pleiotropy is observed as covarying global molecular patterns that define each endosperm. Global coherence was discovered as a covariate coordinator within and between local genotype specific fingerprints. This implies that any of these fingerprints can select its recombinant global phenotype variant, including composition. Introducing the law of coherence, and the movement of gene complexes by chemical fingerprint traits as selectors, introduces a revolution in understanding physiological molecular genetics and plant-breeding.

BACKGROUND The long-term natural history of microscopic colitis remains uncertain. AIM To describe the mortality in a large unselected cohort of patients with microscopic colitis. METHODS All Danish patients above 18 years with an incident diagnosis of microscopic colitis from 2001 to 2018 were identified from nationwide registries and compared to age- and sex-matched controls (variable 1:10 ratio). Patients were categorised according to subtypes: lymphocytic colitis and collagenous colitis. The relative risk of death by any cause was analysed with Cox regression models estimating both crude and comorbidity-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Cause-specific death was evaluated with cumulative incidence functions. An E-value was calculated to address the impact of unmeasured confounding. RESULTS The final cohort consisted of 14 024 patients with microscopic colitis. The mean follow-up was 5.8 (standard deviation SD, 2.9) years and the mean age at diagnosis was 61.1 (SD 13.9) years, 70% were women and 41% were diagnosed with lymphocytic colitis. The main results showed a 25% increased risk of all-cause death in patients with microscopic colitis; however, the relative risk was attenuated to 9% when adjusting for comorbidities (95% CI, 1.05-1.14). The E-value indicates that unmeasured confounding could explain the residual observed increased all-cause mortality. Mortality was significantly increased in patients with both lymphocytic colitis (HR 1.15; 95% CI, 1.08-1.23) and collagenous colitis (HR 1.06; 95% CI, 1.01-1.12) in fully adjusted analyses. The absolute difference in death between patients with microscopic colitis and matches was 0.9% at 1 year, 2.8% at 5 years, 5.0% at 10 years and 3.0% at 15 years. Cumulative incidence functions showed that patients with microscopic colitis were more likely to die due to smoking-related diseases including ischemic heart and lung diseases, but had a significant decreased risk of death due to colorectal cancers (P

Introduction Microscopic colitis is a chronic inflammatory bowel disease characterised by normal or almost normal endoscopic appearance of the colon, chronic watery, non-bloody diarrhoea and distinct histological abnormalities, which identify three histological subtypes, the collagenous colitis, the lymphocytic colitis and the incomplete microscopic colitis. With ongoing uncertainties and new developments in the clinical management of microscopic colitis, there is a need for evidence-based guidelines to improve the medical care of patients suffering from this disorder. Methods Guidelines were developed by members from the European Microscopic Colitis Group and United European Gastroenterology in accordance with the Appraisal of Guidelines for Research and Evaluation II instrument. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists, pathologists and basic scientists, and voted upon using the Delphi method. Results These guidelines provide information on epidemiology and risk factors of microscopic colitis, as well as evidence-based statements and recommendations on diagnostic criteria and treatment options, including oral budesonide, bile acid binders, immunomodulators and biologics. Recommendations on the clinical management of microscopic colitis are provided based on evidence, expert opinion and best clinical practice. Conclusion These guidelines may support clinicians worldwide to improve the clinical management of patients with microscopic colitis. Funding Agencies|UEG Activity Grant

The significantly higher incidence rates of microscopic colitis (MC) in Denmark compared to Sweden remains unexplained.Consecutive patients with newly diagnosed MC in the neighbouring regions of Skåne in 2011-2015 and Zealand in 2010-2016 were prospectively identified. Data on large bowel endoscopies and biopsies rates were retrieved. Information on putative factors were obtained from registers and literature. Interobserver agreement between pathologists from both regions on 40 blinded hematoxylin and eosin (HE)-stained colon biopsies (collagenous colitis (CC), lymphocytic colitis (LC), non-specific inflammation and normal) was evaluated using kappa statistics.The mean annual incidence per 10The incidence of MC and number of cases per colonic biopsy was higher in Zealand and could not be readily explained by endoscopy or biopsy rates, differences in histological assessment or putative risk factors.

OBJECTIVES: Patients with microscopic colitis (MC) have several risk factors for osteoporosis. The prevalence of osteopenia and osteoporosis in MC is unknown. The primary purpose of this study was to evaluate bone mineral status in MC.METHODS: Patients with MC and disease activity within the last 2 years were included. Bone turnover markers were analyzed and bone mineral density (BMD) was measured with Dual Energy X-ray Absorptiometry (DXA) at inclusion and after one year. Medical history, demographics, risk factors for osteoporosis, disease activity and treatment with cumulative budesonide dosage at least 3 years before inclusion was registered. Adrenal function was tested by adrenocortico-tropic hormone (ACTH) and an ACTH stimulation test at inclusion. Results were compared with age and sex-matched controls.RESULTS: Fifty MC patients (44 women) were included. Median age 67 (range 45-93); median disease duration 28 month (range 2-163); median cumulative budesonide dosage 702 mg (range 0-5400). No difference in number of patients with osteoporosis or osteopenia and BMD was detected between groups. The bone mineral formation marker specific alkaline phosphatase was lower in MC than controls 12 (5-69) µg/l versus 16 (10-35) µg/l (p < 0.005). Patients more often smoked (34% versus 10%, p = 0.001). Disease duration and cumulative budesonide dose was associated with lower BMD and T-score in hip (Spearman's rho; p < 0.05) with a cut of point of 2500 mg budesonide predicting osteopenia. Budesonide treatment did not affect adrenal gland function.CONCLUSION: The risk of osteoporosis in patients with MC is not increased. However, DXA scan is recommended in MC patients with known risk factors or active disease requiring longstanding budesonide treatment. Supplementation of calcium and vitamin-D in patients treated with budesonide is recommended.

Microscopic colitis (MC) is the umbrella term for the conditions termed lymphocytic colitis (LC) and collagenous colitis (CC). LC with thickening of the subepithelial collagen band or CC with increased number of intraepithelial T- lymphocytes (IELs) is often seen in MC and may lead to difficulties in correct histological classification. We investigated the extent of overlapping features of CC and LC in 60 cases of MC by measuring the exact thickness of the subepithelial collagen band in Van Gieson stained slides and quantifying number of IELs in CD3 stained slides by digital image analysis. A thickened collagen band was observed in nine out of 29 cases with LC (31%) and an increased number of IELs in all 23 cases of CC (100%). There was no correlation between the thickness of the collagen band and number of IELs. Due to the increased number of IELs in all cases of CC we consider the lymphocytic inflammatory infiltration of the mucosa to be the essential histopathological feature of MC. However, although LC and CC are related due to the lymphocytic inflammation, the non-linear correlation of number of IELs and thickness of the collagenous band indicate differences in their pathogenesis.

To describe a cohort of patients with intestinal failure (IF) and tunnelled catheters in a regional IF unit, treatment and catheter-related complication rates, and to compare the quality of care with previously published results from specialised IF centres in Denmark.A retrospective chart review of an adult IF patient cohort receiving parenteral therapy through tunnelled catheters in a regional IF unit from 2005 to 2014. Demographics, indication, type and frequency of parenteral therapy, dwell time, cause of removal and complications were recorded.Parenteral therapy was provided to 78 patients with a median age of 64 (25-86) years. Numbers increased from seven patients in 2005 to 40 in 2014. The cause of IF was surgical complications (33%), cancer (28%), inflammatory bowel disease (IBD, 15%) and other causes (24%). The median duration of parenteral therapy was 453 days (range: 16-3651 days). One hundred and forty-two tunnelled catheters were inserted. The incidence of catheter-related blood stream infection (CRBSI) was 1.51/1000 days (95% CI: 1.20-1.90) and the incidence of thrombosis was 0.10/1000 days (0.04-0.25). Seventy-two episodes of CRBSI occurred with 89 microorganisms cultured, the most common being coagulase-negative Staphylococcus (n = 25, 28%).The rate of CRBSI did not differ from larger centres in Denmark but the rate of thrombotic events was higher than expected. Parenteral therapy can safely and effectively be offered to patients with IF in smaller centres.

SummaryBackground Bile acid diarrhoea is underdiagnosed and better diagnostic tests are needed. Fasting serum fibroblast growth factor-19 (FGF19) has insufficient diagnostic value, but this may be improved by stimulation. Aim To explore if an impaired FGF19 response identifies primary bile acid diarrhoea. Methods Eight patients with primary bile acid diarrhoea and eight healthy volunteers ingested (i) a meal plus 1250 mg chenodeoxycholic acid (CDCA), (ii) 1250 mg CDCA or (iii) the meal. Blood was sampled at fasting and repeatedly after stimulation. We analysed FGF19 by enzyme-linked immunosorbent assay and bile acids including 7α-hydroxy-4-cholesten-3-one by liquid chromatography-tandem mass spectrometry. Results Stimulation with the meal plus CDCA increased median FGF19 in healthy volunteers from fasting 62 pg/mL [interquartile range (IQR): 41–138] to 99 pg/mL (IQR: 67–147; P = 0.012) after 90 min and peaked after 150 min at 313 pg/mL (IQR: 54–512). This response was impaired in primary bile acid diarrhoea patients [fasting 56 pg/mL (IQR: 42–79); 90 min: 48 pg/mL [IQR: 37–63); 150 min: 57 pg/mL (48–198)]. Receiver operating characteristics (ROCAUC) for fasting FGF19 was 0.55 (P = 0.75) and at 90 min 0.84 (P = 0.02). The difference in FGF19 from fasting to 90 min after the meal plus CDCA separated the groups (ROCAUC 1.0; P = 0.001). 7α-hydroxy-4-cholesten-3-one was elevated in primary bile acid diarrhoea (P = 0.038) and not significantly affected by stimulation. Conclusions The FGF19 response following chenodeoxycholic acid plus meal is impaired in primary bile acid diarrhoea. This may provide a biochemical diagnostic test.

Background Administration and monitoring of biologic therapy to patients with inflammatory bowel disease (IBD) is an increasing burden in gastroenterology outpatient clinics. The aim of this study was to compare the present organisation of biologic therapy to IBD patients in Denmark with the published evidence. Methods A national online survey using SurveyXact was send to all outpatient clinics administering biologic treatment to IBD patients in Denmark in March 2019. It focused on infusion time, post infusion observation and biochemical control of treatment with biologic drugs. A systematic literature search covering the same topics was performed on PubMed in May 2019. Results 21 of 23 clinics completed the survey. Infusion time for infliximab induction was 2 h in all clinics and was reduced to 30 min or 1 h in 60 % and 40% of clinics respectively after ≥ 10 infusions. Vedolizumab infusion time was 30 min in 90% of clinics from start. Ustekinumab infusion time was 1 h in 90% of clinics. Observation time after intravenously administered biologics varied considerably. Only half of the clinics discharged patients on infliximab without post-infusion observation from the start of maintenance treatment increasing to 80% of clinics after ten infusions. About half of the clinics observed patient on vedolizumab maintenance for at least 30 min after 5 infusions. Ten clinics discharged patients immediately after the initial ustekinumab infusion. In 30–60% of clinics, patients were observed 20–120 min after subcutaneous injection of ustekinumab, adalimumab or golimumab. Twenty clinics controlled laboratory parameters prior to every maintenance treatment with infliximab and vedolizumab, no matter of infusion interval, while patients on injection therapy with adalimumab, golimumab and ustekinumab had biochemical tests taken every second to third months. Only two clinics measured trough values and antibodies against biologics routinely and adjusted the dose accordingly to the trough value. The systematic literature search identified 26 relevant articles. These showed that infliximab infusion time of 30 minutes is safe and questioned the necessity of post-infusion observation. There was no consensus on the frequency of biochemical control in patients on biologics. Conclusion Reduction and harmonisation of infusion time, post-infusion and post-injection observation time for patients on biologics could release patient and staff resources.

A deficiency in the ileal hormone fibroblast growth factor 19 (FGF19) has been described in patients with bile acid diarrhoea (BAD), but fasting FGF19 levels have insufficient diagnostic power. We assess whether single postprandial sampling of FGF19 has greater discriminative value than fasting FGF19 for detection of BAD and we evaluate the reproducibility of fasting FGF19.Twenty-six patients consecutively referred to Se homocholic acid retention test (SeHCAT) were included. Serum FGF19 was measured after an overnight fast and again 1 h postprandially and again in the fasting state 1 week later.Nine of 26 patients had SeHCAT less than 10% and fasting FGF19 was lower [median 62 pg/ml, interquartile range (IQR): 47-67] than in the 17 diarrhoea controls with SeHCAT at least 10% (median 103 pg/ml, IQR: 77-135, P=0.006). Postprandial FGF19 in BAD patients (61 pg/ml, IQR: 48-69) was similar to fasting values (P=0.59) and increased insignificantly in diarrhoea controls (137 pg/ml, IQR: 88-182; P=0.25). The difference in postprandial FGF19 between patients with BAD and diarrhoea controls was highly significant (P0.001).The difference in serum FGF19 between groups of patients with BAD and diarrhoea controls is amplified postprandially. Within each group, the difference between fasting and postprandial FGF19 was not statistically significant. Further investigations are warranted on stimulated FGF19 response to elucidate its role in BAD.

BACKGROUND: This study assessed the effects of infliximab (IFX) treatment failure on patient-reported outcomes and explored the influence of using personalized treatment in this situation.METHODS: Sixty-nine Crohn's disease patients with IFX treatment failure were randomized to an intensified IFX regimen (n = 36) or personalized treatment defined by IFX and anti-IFX antibodies (n = 33). Health-related quality of life evaluated with the Short Inflammatory Bowel Disease Questionnaire (IBDQ) and productivity evaluated with the Work Productivity and Activity Impairment Questionnaire (WPAI:CD) were assessed at treatment failure and after 4, 8, 12 and 20 weeks.RESULTS: Median IBDQ score at manifestation of IFX treatment failure was 40 and improved markedly in responders by 11 at weeks 4 and 8 (p < 0.001) and by 13 at weeks 12 and 20 (p < 0.001). Non-responders improved modestly at weeks 12 and 20 (increase of median 4, p < 0.05). Overall activity impairment was high at IFX failure (median 70%) and decreased substantially in responders (40-50%, p < 0.001) and to a lesser extent in non-responders (15-40%, p < 0.05). In employed patients (55%), absenteeism was negligible during the entire study period. However, median presenteeism was 40% at manifestation of IFX failure and decreased only among responders across time (decrease 10-30%, p < 0.05). Although anti-tumour necrosis factor (TNF) therapy was discontinued in most patients handled by personalized treatment, IBDQ and WPAI:CD scores were similar in these patients compared with patients routinely dose-intensified on IFX.CONCLUSION: Regaining low disease activity after IFX failure is necessary for minimizing patient impairment and indirect disease-related costs. A personalized treatment strategy does not have a negative influence on patient-reported outcomes.

BACKGROUND AND AIMS: Intensification of the infliximab (IFX) regimen is recommended if the treatment effect is inadequate. However, the rationale for this is not well defined as the underlying mechanisms vary. The aim of this study was to explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes.METHODS: We performed a post hoc analysis of a randomized clinical trial including 42 Crohn's disease patients with IFX treatment failure, all treated with an intensified IFX regimen (5mg/kg every 4 week) for 12 weeks. Trough serum IFX and anti-IFX Ab concentrations were measured by a homogeneous mobility shift binding assay (HMSA) and a functional cell-based reporter gene assay (RGA) at treatment failure and the end of the trial.RESULTS: Twenty-one patients (50%) regained clinical response on the intensified IFX regimen. The increase in serum trough levels of IFX during treatment intensification was higher among responders than non-responders (RGA, 8.8 versus 3.0 μg/mL, p = 0.035; HMSA, 9.9 versus 4.7 μg/mL, p = 0.040), and differentiated patients by clinical outcome (RGA, area under receiver operating characteristic curve [AUC] 0.75 [0.53-0.97], p = 0.035; HMSA, AUC 0.74 [0.53-0.95], p = 0.042). All responders exhibited an IFX increase ≥2.6 μg/mL (sensitivity 100%, specificity 50%). Anti-IFX Abs detected by HMSA in 13 patients (32%) were often non-functional and became undetectable during IFX intensification. However, even functional anti-IFX Abs detected by RGA in six patients (15%) became undetectable.CONCLUSION: Increase in IFX levels following treatment intensification was associated with improved clinical outcomes, indicating insufficient drug levels in a subgroup of patients. Anti-IFX Abs may become undetectable during treatment intensification, suggesting lowered production or the formation of immune complexes.

Background/Introduction Lymphocytic colitis (LC) and the incomplete form (LCi) are common causes of chronic watery diarrhea. Endoscopy is often inconspicuous, and the diagnosis relies on histopathological assessment of colonic biopsies. Digital Image Analysis (DIA) eliminates interobserver variation. The aim of this study was to establish digital cutoff values for LC and LCi on CD3 stained slides. Material and methods One hundred and six patients with a hematoxylin and eosin (HE) diagnosis of normal colonic mucosa (N = 19), non-specific reactive changes (N = 24), LCi (N = 23) and LC (N = 40) were eligible for analysis. The number of intraepithelial lymphocytes (IELs) reached by DIA in the total surface epithelium and in hot spots of the biopsies was compared with the diagnostic category assigned by the pathologists based on HE stained slides. The digitalized slides were analyzed for number of IELs using Visiopharm Quantitative Digital Pathology software. All digitalized slides were examined manually to identify differences in the approach to the evaluation of the biopsies by the pathologists and DIA. Results The median IEL counts and interquartile range in the total surface epithelium were 3.6 (3.2–4.3), 4.4 (3.4–5.3), 19.8 (16.6–30.0) and 41.3 (37.0–47.8) in normal colon mucosa, mucosa with non-specific reactive changes, LCi and LC, respectively. Discrimination between normal mucosa and non-specific reactive changes was not possible. Digital cutoff values with the best separation between non-LC, LCi and LC were > 13 IELs/100 epithelial cells for LCi and > 36 IELs/100 epithelial cells for LC. These cutoff values resulted in an agreement between the pathologist’s and DIA that was very good with a kappa value of 0.90. Conclusion Despite differences among the approach of DIA and the pathologist’s assessment of IELs in colonic mucosa DIA is able discriminate between the HE based diagnoses of the three subgroups non-LC, LCi and LC with high accuracy.

The diagnosis of microscopic colitis (MC) is based on histologic findings and includes collagenous colitis (CC) and lymphocytic colitis (LC). Incomplete MC (MCi) denotes patients with chronic diarrhea and a normal endoscopy and morphological changes that do not completely meet the histologic criteria of LC or CC. The aim of this study was to investigate the intraobserver and interobserver agreement on the MC subtypes of CC, LC, and MCi and the ability to discriminate MCi from normal and inflammatory bowel disease/nonspecific reactive changes. A single hematoxylin and eosin-stained specimen from biopsies of the following 5 groups were randomly selected and blinded: CC, LC, MCi, inflammatory bowel disease, and normal. Three pathologists independently reviewed the specimens. The specimens were relabeled and reinterpreted 4 months later. Intraobserver and interobserver agreement was evaluated by κ statistics. κ values for intraobserver agreement were good for 5 diagnostic groups varying from 0.70 to 0.83 and very good when simplifying to only 3 diagnostic groups varying from 0.88 to 0.96, separating MC/MCi from non-MC. κ values for interobserver agreement varied from 0.60 to 0.75 for 5 diagnostic groups and 0.81 to 0.89 for 3 diagnostic groups. The study shows that the intraobserver and interobserver agreement is high for discriminating between MC/MCi and non-MC, whereas the ability to discriminate MCi from CC and LC is lower. A revision and consensus on the histologic criteria of the MC subtypes seem warranted.

The development of crop varieties tolerant to growth temperature fluctuations and improved nutritional value is crucial due to climate change and global population growth. This study investigated the metabolite patterns of developing barley seed as a function of genotype and growth temperature for ideal vegetable protein production and for augmented β-glucan production. Seeds from three barley lines (Bomi, lys3.a and lys5.f) were sampled eight times during grain filling and analysed for metabolites using gas chromatography-mass spectrometry (GC-MS). The lys3.a mutation disrupts a regulator gene, causing an increase in proteins rich in the essential amino acid lysine, while lys5.f carries a mutation in an ADP-glucose transporter gene leading to a significant increase in production of mixed-linkage β-glucan at the expense of α-glucan. Unique metabolic patterns associated with the tricarboxylic acid cycle, shikimate-phenylpropanoid pathway, mevalonate, lipid and carbohydrate metabolism were observed for the barley mutants, whereas growth temperature primarily affected shikimate-phenylpropanoid and lipid metabolism. The study applied recently developed GC-MS metabolomics methods and demonstrated their successful application to link genetic and environmental factors with the seed phenotype of unique and agro-economically important barley models for optimal vegetable protein and dietary fibre production.

Anne-Marie Kanstrup Fiehn,1,2 Martin Kristensson,3 Ulla Engel,4 Lars Kristian Munck,5,6 Susanne Holck,4 Peter Johan Heiberg Engel1,6 1Department of Pathology, Roskilde Hospital, Roskilde, 2Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, 3Digital Pathology, Visiopharm, Hørsholm, 4Department of Pathology, Copenhagen University Hospital, Hvidovre, 5Department of Gastroenterology, Koege Hospital, Koege, 6Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Purpose: The aim of this study was to develop an automated image analysis software to measure the thickness of the subepithelial collagenous band in colon biopsies with collagenous colitis (CC) and incomplete CC (CCi). The software measures the thickness of the collagenous band on microscopic slides stained with Van Gieson (VG). Patients and methods: A training set consisting of ten biopsies diagnosed as CC, CCi, and normal colon mucosa was used to develop the automated image analysis (VG app) to match the assessment by a pathologist. The study set consisted of biopsies from 75 patients. Twenty-five cases were primarily diagnosed as CC, 25 as CCi, and 25 as normal or near-normal colonic mucosa. Four pathologists individually reassessed the biopsies and categorized all into one of the abovementioned three categories. The result of the VG app was correlated with the diagnosis provided by the four pathologists. Results: The interobserver agreement for each pair of pathologists ranged from Κ-values of 0.56–0.81, while theΚ-value for the VG app vs each of the pathologists varied from 0.63 to 0.79. The overall agreement between the four pathologists wasΚ=0.69, while the overall agreement between the four pathologists and the VG app wasΚ=0.71. Conclusion: In conclusion, the Visiopharm VG app is able to measure the thickness of a subepithelial collagenous band in colon biopsies with an accuracy comparable to the performance of a pathologist and thereby provides a promising supplementary tool for the diagnosis of CC and CCi and in particular for research. Keywords: microscopic colitis, collagenous colitis, incomplete collagenous colitis, automated image analysis

Plant photosynthesis and grain production is the basis for a sustainable environment supporting human life that should not be compromised for the generations to come. It is expected that world grain production has to increase by about 50% up to the year 2050 to support a population of up to 11 billion people. The key question is how and if such a change can be introduced for a sustainable intensification with a minimum of damage to environment and human health still keeping the production potential intact? The combination of new efficient analytical methods in molecular biology (genomics, proteomics) with new megavariate instrumental phenotypic analyses (phenomics, metabolomics) evaluated by pattern recognition computer tools (chemometrics) creates a revolution in an integrated science of plant breeding, grain production and environment. The new concept makes GMO (genetic modified organisms) breeding sustainable and uncontroversial when utilizing certified gene resources and vectors within the plant kingdom . In order to properly exploit the new biologically adapted grain varieties obtained by integrated breeding, human wearing of the planet must be diminished by changing the related infrastructure. In implementing these changes one has to create economic incentives to channel the present rising wealth of the world economy into investments in connecting rural and urban living by the concept of the bio-refinery that could conserve energy and recycle organic waste and water. Such an integrated improvement in infrastructure is the basis for securing clean water and energy, fertile soils with vital microorganisms, biodiversity, green cities, food supply, and social rest.

Microscopic colitis (MC) is an inflammatory bowel disease presenting with chronic, non-bloody watery diarrhoea and few or no endoscopic abnormalities. The histological examination reveals mainly two subtypes of MC, lymphocytic or collagenous colitis. Despite the fact that the incidence in MC has been rising over the last decades, research has been sparse and our knowledge about MC remains limited. Specialists in the field have initiated the European Microscopic Colitis Group (EMCG) with the primary goal to create awareness on MC. The EMCG is furthermore a forum with the intention to promote clinical and basic research. In this article statements and comments are given that all members of the EMCG have considered being of importance for a better understanding of MC. The paper focuses on the newest updates in epidemiology, symptoms and diagnostic criteria, pathophysiology and highlights some unsolved problems. Moreover, a new treatment algorithm is proposed on the basis of new evidence from well-designed, randomized control trials.

When predicting the chemical composition of food samples from near-infrared spectroscopy using partial least squares regression, deep knowledge of the origin of the information is not present. We are aiming at opening a Pandora's box of how the prediction of protein proceeds in a unique set of chemically diverse barley mutant samples. An external validation of the sources of co-variation in nature that are exploited by chemometric models would give a framework for manipulating the deciding information to make expensive calibration more economical. The barley samples were supplemented by two designed data sets: one mirroring the coarse composition of the barley samples by mixing six main chemical components and one set where the biological covariance between the six chemical components had been reduced. The three original data sets give remarkably comparable prediction models, albeit their regression coefficients are quite different. The origin of the prediction ability of the data is elucidated by splitting the natural barley samples into two parts: one based on simulated biology extracted from a set of chemical mixtures, and the residual after the chemistry has been removed from the raw data. As much as 98.1% of the spectral information in the natural barley data is explained through the simulated biology, leaving as little as 1.9% of the spectral information for the unexplained biological variation and noise. However, unexplained biological variation still gives a fair prediction of protein (RMSECV = 1.23 and r2 = 0.80, compared with RMSECV = 0.46 and r2 = 0.97 for the natural data), and it gives a clear principal component analysis separation of the three genotype classes. The results were interpreted by conducting spectral inspection on the origin of the unique covariate patterns appearing in self-organised biological systems that should motivate researchers and industry to investigate the compressive effect that the model has on the essential deterministic biological data. Copyright © 2012 John Wiley & Sons, Ltd.

Nielsen OH, Seidelin JB, Munck LK, Rogler G (Herlev Hospital, University of Copenhagen, Copenhagen; Koge Hospital, University of Copenhagen, Copenhagen, Denmark; and University Hospital of Zurich, Zurich, Switzerland). Use of biological molecules in the treatment of inflammatory bowel disease (Review). J Intern Med 2011; 270: 15–28. The introduction of biological agents (i.e. antitumour necrosis factor-α and anti-integrin treatments) for the treatment of inflammatory bowel disease (IBD) [i.e. Crohn’s disease (CD) and ulcerative colitis] has led to a substantial change in the treatment algorithms and guidelines, especially in CD. However, many questions still remain about the true efficacy and the best treatment regimens. Thus, a need for further treatment options still exists as up to 40% of IBD patients treated with the presently available biologicals do not have positive clinical responses. Better patient selection might maximize the clinical benefit for those in most need of an effective therapy to avoid disabling disease whilst also minimizing the complications associated with therapy. Further, the ‘trough-level strategy’ may help clinicians to optimize therapy and to avoid loss of response and/or immunogenicity. The idea behind this dosage regimen is that correct dosing must ensure that the patient’s lowest level of drug concentration (i.e. the trough level) occurring just before the next drug administration is high enough for the full effect to be seen. Controversy continues regarding the appropriate use of biologicals; therefore, in this review, we focus on considerations that might lead to a more rational strategy for antitumour necrosis factor-α agents in IBD, emphasizing the situations in which the risks may outweigh the benefits. Finally, the need for an appropriate strategy for stopping biological treatment is discussed.

Background and aim: Microscopic colitis (MC) is an inflammatory disease of the bowel, hypothetically induced by an immunologic response to a luminal microbial agent. We aimed to characterize the mi...

An extension of chemometric theory was experimentally explored to explain the physiochemical basis of the very high efficiency of soft modelling of data from nature. Soft modelling in self-organisation was interpreted by studying the unique chemical patterns of mutants in an isogenic barley model on endosperm development. Extremely reproducible, differential Near Infrared (NIR) spectral patterns specifically overviewed the effect on cell composition of each mutant cause. Extended Canonical Variates Analysis (ECVA) classified spectra in wild type, starch and protein mutants. The spectra were interpreted by chemometric data analysis and by pattern inspection to morphological, genetic, molecular and chemical information. Deterministic chemical reactions were defined in the glucan pathway. A drastic mutation in a gene controlling the starch/β-glucan composition changed water activity that introduced a diffusive, stochastic effect on the catalysis of all active enzymes. 'Decision making' in self-organisation is autonomous and performed by the soft modelling of the chemical deterministic and stochastic reactions in the endosperm cell as a whole. Uncertainty in the analysis of endosperm emergence was experimentally delimited as the 'indeterminacy' in local molecular path modelling 'bottom up' and the 'irreducibility' of the phenomenological NIR spectra 'top down'. The experiment confirmed Ilya Prigogine's interpretation of self-organisation by his dynamic computer model programmed with a self-modeled non-local extension of quantum mechanics (QM). The significance of self-organisation explained by Prigogine here interpreted as physiochemical soft modelling introduces a paradigm shift in macroscopic science that forwards a major argument for soft mathematical modelling and chemometrics to obtain full scientific legitimacy.