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Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that obstructs the bile ducts and causes liver cirrhosis and cholangiocarcinoma. Efficient surrogate markers are required to measure disease progression. The cytokeratin 7 (K7) load in a liver specimen is an independent prognostic indicator that can be measured from digitalized slides using artificial intelligence (AI)-based models.A K7-AI model 2.0 was built to measure the hepatocellular K7 load area of the parenchyma, portal tracts, and biliary epithelium. K7-stained PSC liver biopsy specimens (n = 295) were analyzed. A compound endpoint (liver transplantation, liver-related death, and cholangiocarcinoma) was applied in Kaplan-Meier survival analysis to measure AUC values and positive likelihood ratios for each histological variable detected by the model.The K7-AI model 2.0 was a better prognostic tool than plasma alkaline phosphatase-ALP, fibrosis stage evaluated by Nakanuma classification, or K7 score evaluated by a pathologist based on the AUC values of measured variables. A combination of parameters, such as portal tract volume and area of K7-positive hepatocytes analyzed by the model, produced an AUC of 0.81 for predicting the compound endpoint. Portal tract volume measured by the model correlated with the histological fibrosis stage.The K7-staining of histological liver specimens in PSC provides significant information on disease outcomes through objective and reproducible data, including variables that cannot be measured by a human pathologist. The K7-AI model 2.0 could serve as a prognostic tool for clinical endpoints and as a surrogate marker in drug trials. This article is protected by copyright. All rights reserved.

Introduction Although sporadic non-ampullary duodenal adenomas (SNADA) are rare, with the risk of progression to cancer, they deserve therapy. Endoscopic therapy of SNADA is effective, but with the increased risk of complications, endotherapy should be performed in high-volume units. The results of endotherapy of SNADA in our unit are presented. Patients and methods A total of 97 patients with SNADA had endoscopic resection in 2005-2021 and control endoscopies between 3 and 24 months. Snare polypectomy, endoscopic mucosal resection (EMR), endoscopic band ligation (EBL) and endoloop were used (en bloc 37% and piecemeal 63%). In cases of residual/recurrent adenomas, endotherapy was repeated. Results The median size of the adenoma was 12 (5-60) mm and most polyps were sessile (25%) or flat (65%). Primary endotherapy eradicated adenomas in 57 (59%) cases. Residual and recurrence rates were 24% (n = 23) and 17% (n = 16) with successful endotherapy in 16 (70%) and 13 (81%) patients. Endotherapy was successful in 86 (89%) patients after a median (range) follow-up of 23 (1-166) months. Four out of 11 patients with failed endotherapy had surgery; seven patients were not fit for surgery. There were no disease-specific deaths or carcinoma. Eleven patients (11%) suffered from complications: perforation requiring surgery (n = 1), sepsis (n = 1), postprocedure bleeding (n = 7), cardiac arrest (n = 1) and coronary infarct (n = 1). The thirty-day mortality was zero. Colonoscopy was performed on 67 (69%) patients with neoplastic lesions in 33% patients during follow-up. Conclusions Endotherapy of SNADA is effective and safe. Repeat endotherapy in residual and recurrent adenomas is successful. Careful patient selection is mandatory.

Background and aims Therapeutic drug monitoring (TDM) may optimize biologic and thiopurine therapies in inflammatory bowel disease (IBD). The study aimed to investigate implementation and utilization of TDM in Scandinavia. Methods A web-based questionnaire on the use of TDM was distributed to Scandinavian gastroenterologists via the national societies. Results In total, 297 IBD physicians prescribing biologic therapies, equally distributed between community and university hospitals, were included (response rate 42%) (Norway 118 (40%), Denmark 86 (29%), Sweden 50 (17%), Finland 33 (11%), Iceland 10 (3%)). Overall, TDM was applied during biologic therapies by 87%, and for TNF-inhibitors >90%. Among the users, reactive and proactive TDM were utilized by 90% and 63%, respectively. Danish physicians were significantly less inclined to use TDM compared to other Scandinavian countries; (58% vs 98%); OR 0.03 [0.01-0.09], p < 0.001). Reactive TDM was commonly applied at primary (74%) and secondary (99%) treatment failure. Proactive TDM was used by 80% during maintenance therapy and 56% during induction and more commonly utilized in Norway (p < 0.001), and by physicians managing >10 IBD patients/week (p = 0.005). TDM scenarios were interpreted in accord with available evidence but with discrepancies for proactive TDM. The main barriers to TDM were lack of guidelines (51%) and time lag between sampling and results (49%). TDM of thiopurines was routinely used by 87%. Conclusion TDM of biologic and thiopurine therapies has been broadly implemented into clinical practice in Scandinavia. However, physicians call for TDM guidelines detailing indications and interpretations of test results along with improved test response times. Funding Agencies|Akershus University Hospital

Background Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease that may lead to liver cirrhosis or cholangiocarcinoma. Liver histology and fibrosis stage are predictive markers of disease progression, and histological cirrhosis is defined as a significant endpoint. PSC-specific histological scoring methods are lacking at present. We aimed to develop a tailored classification system for PSC, the PSC histoscore, based on histological features associated with disease progression. Methods In total, 300 PSC patients diagnosed between 1988 and 2018 were enrolled; their data were collected from the PSC registry (Helsinki University Hospital), and liver specimens were obtained from the Biobank of Helsinki. Five histological features included in the adapted Nakanuma scoring system and three additional parameters typical for PSC histology were evaluated and compared with the clinical and laboratory data. A compound endpoint consisting of liver transplantation, development of cholangiocarcinoma, or death was used as outcome measurement. Results Stage (fibrosis, bile duct loss, ductular reaction, and chronic cholestasis) and grade (portal inflammation, portal edema, hepatitis activity, and cholangitis activity) parameters were found to be independent predictive risk factors for the compound endpoint (P < 0.001). High disease grade (2-6) and stage (2-4) better correlated with clinical endpoints when evaluated with the PSC histoscore system compared to the adapted Nakanuma classification. The risk for disease progression in sequential endoscopic retrograde cholangiography (ERC) examinations was increased with elevated total PSC histoscores. Conclusion The PSC histoscore is a novel histological classification system for PSC. Our findings support the applicability of liver histology as a marker for disease progression.

Publisher Copyright: © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Objectives: The development of intestinal failure-related complications in Finnish adults is unknown. This study aimed to investigate the incidence of catheter-related bloodstream infections (CRBSI), and the longitudinal changes in biochemical liver and kidney tests in a nationwide cohort. Materials and methods: The search for Finnish adults with intestinal failure (IF) utilized a survey to Finnish health-care providers (n = 111) with the potential to provide long-term parenteral support (PS) for adult IF. Our nationwide, cross-sectional cohort included all IF patients aged ≥ 18 years who had received PS for ≥ 120 d in 2017. Data regarding CRBSI and biochemical liver and kidney tests were collected from patient records at the start of PS up to the latest available measurement in 2017. Results: In the nationwide cohort of 52 patients, the CRBSI incidence was 1.35/1000 catheter days. Seventy-three percent of CRBSI in a long-term catheter led to catheter replacement. During a median PS duration of 27.5 (interquartile range [IQR] 11.3–57.3) months, a statistically significant median change occurred in estimated glomerular filtration rate (eGFR; −8.5 ml/min/1.73 m2, IQR −30–7, p =.005) and alkaline phosphatase (ALP; 26 U/l, IQR −11–95, p =.019). In a multiple regression model for eGFR at data collection, baseline eGFR and age were strong explanatory variables. Conclusions: Incidence of CRBSI, but not treatment strategies, in this nationwide adult IF population correspond well to those reported from specialized centers. Decreased kidney function and abnormal liver test results are frequent findings, and even more so over time, emphasizing the importance of regular monitoring.

Roughly 10% - 20% of pancreatic cancer patients are candidates for curative intent surgical treatment. In the 2000s, many studies showed similar survival rates comparing pancreatic surgery with or without vein resection and reconstruction. The aim was to identify the best method of venous reconstruction.This was a retrospective cohort study. A total of 1 375 patients undergoing pancreatectomy between 2005 and 2018 were identified. Patients undergoing a combined pancreatic resection and venous reconstruction were included retrospectively. When tumour infiltration to the portal/superior mesenteric vein was detected, excision and reconstruction with tangential suturing/patch, end to end anastomosis, or a spiral graft from the great saphenous vein was performed. Next, 90 day and long term survival and outcomes across reconstruction techniques were analysed.Overall, 198 patients had venous involvement visible in pre-operative scans or detected during surgery, broken down as follows: 171 (86%) pancreaticoduodenectomy, 12 (6%) total pancreatectomy, and 15 (8%) distal pancreatectomy. In total, 69 (35%) spiral graft reconstructions, 77 (39%) end to end anastomoses, and 52 (26%) tangential/patch reconstructions were performed. Tumour histology revealed pancreatic adenocarcinomas in 162 (82%) patients, intraductal mucinous pancreatic neoplasia in 14 (7%), cholangiocarcinoma in five (3%), neuro-endocrine neoplasia in nine (5%), and eight other diagnoses. Overall, 183 (92%) were malignant and 15 (8%) benign. Two patients died within 90 days, one in hospital and one on post-operative day 38 due to thrombosis of the superior mesenteric vein and intestinal necrosis, a Clavien-Dindo grade 5 complication. In addition, 50 (23%) patients had Clavien-Dindo grade 3 - 4 complications. No differences in complications comparing vein reconstruction techniques or in the long term survival of pancreatectomy patients with or without venous reconstruction were detected.The spiral graft technique, used when more advanced venous infiltration occurs, does not increase complications, with outcomes mirroring those accompanying shorter venous resections.

Introduction: The prevalence of immune-mediated diseases has increased in the past decades and despite the use of biological treatments all patients do not achieve remission. The aim of this study was to characterise the reasons for short interruptions during treatment with two commonly used TNF-inhibitors infliximab and adalimumab and to analyse the possible effects of the interruptions on immunisation and switching the treatment. Material and methods: This case-control study was based on retrospective analyses of patient records and a questionnaire survey to clinicians. A total of 370 patients (194 immunised cases and 172 non-immunised controls, 4 excluded) were enrolled from eight hospitals around Finland. Eleven different diagnoses were represented, and the largest patient groups were those with inflammatory bowel or rheumatic diseases. Results: Treatment interruptions were associated with immunisation in patients using infliximab (p

Objectives: Despite recombinant interferon-λ 4 (IFN-λ4) demonstrating anti-viral activity in vitro and the ancestral functional gene (IFNL4) being conserved in all other primates, there has been speculation that IFN-λ4 may be detrimental in humans. In light of recent rekindled interest in humoral immunity, this study aimed at evaluating the impact of baseline characteristics, including IFNL4, on antibody levels to hepatitis C virus (HCV). Materials and methods: Pretreatment sera from 279 well-characterized North European Caucasians with chronic HCV genotype 2 or 3 infection having undergone liver biopsy were analyzed regarding IFNL4 (rs12979860) and anti-HCV antibody levels using a commercially available assay. Results: Patients producing IFN-λ4 had higher signal to cut-off (S/CO) anti-HCV antibody ratios as compared with those lacking IFN-λ4 (IFNL4 rs12979860 CT/TT versus CC, ps = −0.14, p =.02) was noted. In multivariate analysis IFN-λ4, gender, steatosis and viral load remained independently associated. Conclusions: To our knowledge, this is the first report that demonstrates that the ability to produce IFN-λ4, in addition to male gender, absent/mild steatosis, and lower viral load, augments antibody levels against HCV. This indicates that IFN-λ4 may be associated with T helper cell 2 (Th2) immune skewing, which might have clinical implications beyond HCV infection. ClinicalTrials.gov Identifier: NCT00143000.

Background In ulcerative colitis, a pouchitis is the most common long-term adverse effect after proctocolectomy and ileal pouch-anal anastomosis. Approximately 5% of patients develop chronic antibiotic-dependent or antibiotic-refractory pouchitis without any effective treatment. The aim of this trial was to investigate the efficacy and safety of fecal microbiota transplantation in the treatment of chronic pouchitis. Methods This was a single-center, double-blinded, parallel group trial comparing donor fecal microbiota transplantation with placebo (autologous transplant) in chronic pouchitis. Twenty-six patients were recruited at the Helsinki University Hospital between December 2017 and August 2018 and were randomly allocated a 1:1 ratio to either donor fecal microbiota transplantation or placebo. The protocol included 2 transplantations into the pouch on weeks 0 and 4, and patients were followed up for 52 weeks. Results Nine patients in the intervention group and 8 patients in the placebo group relapsed during the 52-week follow-up, and the relapse-free survival did not differ between the groups (P = 0.183, log-rank; hazard ratio, 1.90 [95% confidence interval, 0.73-4.98; P = 0.190]). In the subgroup analysis of patients using continuous antibiotics before the study, the relapse-free survival was shorter in the intervention group (P = 0.004, log-rank; hazard ratio, 13.08 [95% confidence interval, 1.47-116.60; P = 0.021]). No major adverse effects were reported. Conclusions The fecal microbiota transplantation treatment regime used in our study was not effective in the treatment of chronic pouchitis. The safety profile of fecal microbiota transplantation was good. ClinicalTrials.gov identifier NCT03378921.

Background & aims: Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease frequently coexist. While several blood-based indices exist for the detection of NAFLD, few studies have examined how alcohol use possibly impacts their diagnostic performance. We analysed the effects of alcohol use on the performance of indices for detecting fatty liver disease (FLD). Methods: We included participants from the Cardiovascular Risk in Young Finns Study (Finnish sample) and KORA study (German sample) who underwent abdominal ultrasound or magnetic resonance imaging, respectively, for detection of FLD and had serum analyses available for calculation of Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), Lipid Accumulation Product (LAP), and Dallas Steatosis Index (DSI). Alcohol use was estimated by questionnaires as mean daily consumption and binge drinking (Finnish sample only). Predictive performance for FLD was assessed according to alcohol consumption. Results: The study included 1426 (Finnish sample) and 385 (German sample) individuals, of which 234 (16%) and 168 (44%) had FLD by imaging. When alcohol consumption was 50 g/day). AUROCs decreased to 0.74–0.80 in the highest binge-drinking category (>2 times/week). Alcohol use correlated with FLI and LAP (r-range 0.09–0.16, p-range

Background and aims There are limited comparative data for infliximab and vedolizumab in inflammatory bowel disease patients. Methods We conducted a systematic review and meta-analysis to compare the efficacy and safety of infliximab and vedolizumab in adult patients with moderate-to-severe Crohn's disease or ulcerative colitis. Results We identified six eligible Crohn's disease and seven eligible ulcerative colitis trials that randomised over 1900 participants per disease cohort to infliximab or vedolizumab. In the Crohn's disease and ulcerative colitis cohorts, infliximab yielded better efficacy than vedolizumab for all analysed outcomes (CDAI-70, CDAI-100 responses, and clinical remission for Crohn's disease and clinical response and clinical remission for ulcerative colitis) during the induction phase, with non-overlapping 95% confidence intervals. In the maintenance phase, similar proportions of infliximab- or vedolizumab-treated patients achieved clinical response, clinical remission, or mucosal healing in both Crohn's disease and ulcerative colitis. For the safety outcomes, rates of adverse events, serious adverse events, and discontinuations due to adverse events were similar in infliximab- and vedolizumab-treated patients in both diseases. The infection rate was higher in infliximab for Crohn's disease and higher in vedolizumab when treating patients with ulcerative colitis. There was no difference between the treatments in the proportions of patients who reported serious infections in both indications. Conclusions Indirect comparison of infliximab and vedolizumab trials in adult patients with moderate-to severe Crohn's disease or ulcerative colitis demonstrated that infliximab has better efficacy in the induction phase and comparable efficacy during the maintenance phase and overall safety profile compared to vedolizumab.

Parvoviruses are single-stranded DNA viruses, infecting many animals from insects to humans. Human parvovirus B19 (B19V) causes erythema infectiosum, arthropathy, anemia, and fetal death, and human bocavirus (HBoV) 1 causes respiratory tract infections, while HBoV2-4 are enteric. Parvoviral genomes can persist in diverse non-permissive tissues after acute infection, but the host-cell tropism and the impact of their tissue persistence are poorly studied. We searched for parvoviral DNA in a total of 427 intestinal biopsy specimens, as paired disease-affected and healthy mucosa, obtained from 130 patients with malignancy, ulcerative colitis (UC), or adenomas, and in similar intestinal segments from 55 healthy subjects. Only three (1.6%) individuals exhibited intestinal HBoV DNA (one each of HBoV1, 2, and 3). Conversely, B19V DNA persisted frequently in the intestine, with 50, 47, 31, and 27% detection rates in the patients with malignancy, UC, or adenomas, and in the healthy subjects, respectively. Intra-individually, B19V DNA persisted significantly more often in the healthy intestinal segments than in the inflamed colons of UC patients. The highest loads of B19V DNA were seen in the ileum and colon specimens of two healthy individuals. With dual-RNAscope in situ hybridization and immunohistochemistry assays, we located the B19V persistence sites of these intestines in mucosal B cells of lymphoid follicles and vascular endothelial cells. Viral messenger RNA transcription remained, however, undetected. RNA sequencing (RNA-seq) identified 272 differentially expressed cellular genes between B19V DNA-positive and -negative healthy ileum biopsy specimens. Pathway enrichment analysis revealed that B19V persistence activated the intestinal cell viability and inhibited apoptosis. Lifelong B19V DNA persistence thus modulates host gene expression, which may lead to clinical outcomes.

Background & Aims: Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow-up strategies in PSC with the hypothesis that regular imaging improves survival. Methods: We collected retrospective data from 2975 PSC patients from 27 centres. Patients were followed from the start of scheduled imaging or in case of clinical follow-up from 1 January 2000, until death or last clinical follow-up alive. The primary endpoint was all-cause mortality. Results: A broad variety of different follow-up strategies were reported. All except one centre used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centres used scheduled endoscopic retrograde cholangiopancreatography (ERCP) in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow-up, was 0.61 (0.47-0.80) for scheduled imaging with and without ERCP; 0.64 (0.48-0.86) for US/MRI and 0.53 (0.37-0.75) for follow-up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high-grade dysplasia as a time-dependent covariate, HR 0.57 (0.44-0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years of follow-up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed. Conclusions: Follow-up strategies vary considerably across centres. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumour detection and increased endoscopic treatment of asymptomatic benign biliary strictures. Funding Agencies: Swedish Cancer Society; Stockholm County Council; Cancer Research Funds of Radiumhemmet

Background Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by biliary strictures, cholestasis, and a markedly increased risk of cholangiocarcinoma. New markers for the screening and differential diagnosis of PSC are needed. In this pilot study, we have analyzed both the bile and serum proteomic profiles of 80 PSC patients and non-PSC controls (n = 6 for bile and n = 18 for serum). Aim The aim of this study was to discover candidates for new biomarkers for the differential diagnosis of PSC. Methods Bile and serum samples were processed and subsequently analyzed using ultra performance liquid chromatography-ultra definition mass spectrometry (UPLC-UDMSE). Further analysis included statistical analyses such as receiver operating characteristic curve analysis as well as pathway analysis using Ingenuity Pathway Analysis. Results and conclusions In bile, we discovered 64 proteins with significantly different levels between the groups, with fold changes of up to 129. In serum, we discovered 112 proteins with significantly different levels. Receiver operating characteristic curve analysis found multiple proteins with high area under the curve values, up to 0.942, indicating that these serum proteins are of value as new non-invasive classifiers of PSC. Pathway analysis revealed multiple canonical pathways that were enriched in the dataset, which have roles in bile homeostasis and metabolism. We present several serum proteins that could serve as new blood-based markers for the diagnosis of PSC after further validation. The measurement of serum levels of these proteins could be of use in the screening of patients with suspected PSC.

Objective: Long-term evidence on ustekinumab treatment response and persistence in patients with Crohn’s disease in a real-world setting is scarce. We performed a retrospective nationwide chart review study of long-term clinical outcomes in Crohn’s disease patients treated with ustekinumab. Methods: The study was conducted in 17 Finnish hospitals and included adult Crohn’s disease patients who received an initial intravenous dose of ustekinumab during 2017–2018. Disease activity data were collected at baseline, 16 weeks, and 1 year from health records. Results: The study included 155 patients. The disease was stricturing or penetrating in 69 and 59% had prior Crohn’s disease-related surgeries, and 97% had a treatment history of at least one biologic agent. Of 93 patients with ≥1 year of follow-up, 77 (83%) were still on ustekinumab at 1 year. In patients with data available, from baseline to the 1-year follow-up the simple endoscopic score for Crohn’s disease (SES-CD) decreased from 10 to 3 (P = 0.033), C-reactive protein from 7 to 5 mg/L, (P

Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2 bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs., Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.

Background The European Society of Gastrointestinal Endoscopy recommends rectal indomethacin or diclofenac before endoscopic retrograde cholangiopancreatography (ERCP) to prevent post-ERCP pancreatitis. However, data on the prophylactic effect in patients with primary sclerosing cholangitis (PSC) are lacking. Methods This was a retrospective case-control study. In 2009-2018, a total of 2000 ERCPs were performed in 931 patients with PSC. Case procedures (N = 1000 after November 2013) were performed after administration of rectal diclofenac. Control procedures (N = 1000 before November 2013) were performed with the same indication but without diclofenac. Acute post-ERCP pancreatitis and other ERCP-related adverse events (AEs) were evaluated. Results Post-ERCP pancreatitis developed in 49 (4.9%) procedures in the diclofenac group and 62 (6.2%) procedures in the control group (p = 0.241). No difference existed between the groups in terms of the severity of pancreatitis or any other acute AEs. The risk of pancreatitis was elevated in patients with native papilla: 11.4% in the diclofenac group and 8.7% in the control group (p = 0.294). In adjusted logistic regression, diclofenac did not reduce the risk of pancreatitis (odds ratio (OR) = 1.074, 95% confidence interval 0.708-1.629, p = 0.737). However, in generalised estimation equations with the advanced model, diclofenac seemed to diminish the risk of pancreatitis (OR = 0.503) but not significantly (p = 0.110). Conclusion In this large patient cohort in a low-risk unit, diclofenac does not seem to reduce the risk of post-ERCP pancreatitis in patients with PSC. The trend in the pancreatitis rate after ERCP is decreasing. The evaluation of the benefits of diclofenac among PSC patients warrants a randomised controlled study targeted to high-risk patients and procedures.

Background and Aims Primary sclerosing cholangitis (PSC) is associated with increased risk of cholangiocarcinoma (CCA). Early and accurate CCA detection represents an unmet clinical need as the majority of patients with PSC are diagnosed at an advanced stage of malignancy. In the present study, we aimed at establishing robust DNA methylation biomarkers in bile for early and accurate diagnosis of CCA in PSC. Approach and Results Droplet digital PCR (ddPCR) was used to analyze 344 bile samples from 273 patients with sporadic and PSC-associated CCA, PSC, and other nonmalignant liver diseases for promoter methylation of cysteine dioxygenase type 1, cannabinoid receptor interacting protein 1, septin 9, and vimentin. Receiver operating characteristic (ROC) curve analyses revealed high AUCs for all four markers (0.77–0.87) for CCA detection among patients with PSC. Including only samples from patients with PSC diagnosed with CCA ≤ 12 months following bile collection increased the accuracy for cancer detection, with a combined sensitivity of 100% (28/28) and a specificity of 90% (20/203). The specificity increased to 93% when only including patients with PSC with longtime follow-up (> 36 months) as controls, and remained high (83%) when only including patients with PSC and dysplasia as controls (n = 23). Importantly, the bile samples from the CCA-PSC ≤ 12 patients, all positive for the biomarkers, included both early-stage and late-stage CCA, different tumor growth patterns, anatomical locations, and carbohydrate antigen 19-9 levels. Conclusions Using highly sensitive ddPCR to analyze robust epigenetic biomarkers, CCA in PSC was accurately detected in bile, irrespective of clinical and molecular features, up to 12 months before CCA diagnosis. The findings suggest a potential for these biomarkers to complement current detection and screening methods for CCA in patients with PSC.

Background and Aims: Gastroesophageal reflux disease (GERD) is associated with an increased risk of cancer of the upper gastrointestinal tract. This study aimed to assess whether and to what extent a negative upper endoscopy in patients with GERD is associated with decreased incidence and mortality in upper gastrointestinal cancer (ie, esophageal, gastric, or duodenal cancer). Methods: We conducted a population-based cohort study of all patients with newly diagnosed GERD between July 1, 1979 and December 31, 2018 in Denmark, Finland, Norway, and Sweden. The exposure, negative upper endoscopy, was examined as a time-varying exposure, where participants contributed unexposed person-time from GERD diagnosis until screened and exposed person-time from the negative upper endoscopy. The incidence and mortality in upper gastrointestinal cancer were assessed using parametric flexible models, providing adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Among 1,062,740 patients with GERD (median age 58 years; 52% were women) followed for a mean of 7.0 person-years, 5324 (0.5%) developed upper gastrointestinal cancer and 4465 (0.4%) died from such cancer. Patients who had a negative upper endoscopy had a 55% decreased risk of upper gastrointestinal cancer compared with those who did not undergo endoscopy (HR, 0.45; 95% CI, 0.43–0.48), a decrease that was more pronounced during more recent years (HR, 0.34; 95% CI, 0.30–0.38 from 2008 onward), and was otherwise stable across sex and age groups. The corresponding reduction in upper gastrointestinal mortality among patients with upper endoscopy was 61% (adjusted HR, 0.39; 95% CI, 0.37–0.42). The risk reduction after a negative upper endoscopy in incidence and mortality lasted for 5 and at least 10 years, respectively. Conclusions: Negative upper endoscopy is associated with strong and long-lasting decreases in incidence and mortality in upper gastrointestinal cancer in patients with GERD.

Background: In the inflammatory bowel diseases, chronic inflammation predisposes to dysplasia and colorectal carcinoma, leading to the need of surveillance colonoscopies. The most-used marker of colonic inflammation is faecal calprotectin. Its correlation with endoscopic and histological findings is well-documented. In this study, we evaluated the role of sequential faecal calprotectin measurements in predicting colorectal dysplasia, to identify patients with increased risk of dysplasia or colonic malignancy in ulcerative colitis. Methods: We collected the faecal calprotectin measurements and colorectal histology reports of patients with ulcerative colitis treated in Helsinki University Hospital (Helsinki, Finland) between 2007 and 2017, with a focus on IBD-associated neoplasia, inflammatory activity, and sporadic adenomas. Using the time-weighted AUC of faecal calprotectin as a marker of inflammatory burden, we tested the performance of faecal calprotectin to predict the risk for colorectal neoplasia. Results: In total, 982 patients with ulcerative colitis were included. Of them, 845 had pancolitis and 127 concomitant primary sclerosing cholangitis. Forty-one patients (4%) had IBD-associated colorectal dysplasia and seven (0.7%) developed adenocarcinoma. In patients with constantly elevated faecal calprotectin level (>500 mu g/g), colorectal neoplasia was more frequent compared to those with low (

Inflammatory bowel disease (IBD), once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.

Funding Information: Financial support: The study was supported by a grant from State funding for University-level health research TYH2016208 (MF). https://hussote.sharepoint.com/sites/00004/Tutkimusrahoitus/Sivut/default.aspx The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright: © 2022 Färkkilä et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background and aims Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease that leads to bile duct strictures, cholestasis, and biliary cirrhosis. PNPLA3 (patatin-like phospholipase domain containing 3), regulates cellular lipid synthesis by converting lysophosphatidic acid into phosphatidic acid. Isoleucine mutation to methionine at position 148 (I148M) causes a loss of this function. Only two studies, with contradictory results, have evaluated the role of PNPLA3 in PSC. The rs738409(G) variant of PNPLA3 has been associated with an increased risk for transplantation in male patients with dominant strictures (DS). The study aimed to evaluate the PNPLA3 allele frequency effect on the clinical outcomes, progression, and prognosis of PSC. Furthermore, we analyzed the impact of PNPLA3 on phospholipid and bile acid composition to evaluate the effect of the PNPLA3 status on UDCA response. Patients and methods We recruited 560 patients prospectively and collected clinical and laboratory data as well as liver histology and imaging findings. PNPLA3 (CC, CG, GG) alleles were analyzed with TaqManTM. We also analyzed bile acids (BA), cholesterol and phospholipids and individual BA from a sample aspirated during endoscopic retrograde cholangiography (ERC). Results Among the recruited patients, 58.4%, 35.7% and 5.9% had the wild (CC), heterozygous (CG) and homozygous (GG) alleles, respectively. The PNPLA3 haplotype did not impact bile composition or individual BA. In addition, we found no differences in age at diagnosis, disease progression, liver fibrosis or survival between the cohorts. Conclusions The PNPLA3 I148M variant had no significant impact on on bile composition, including UDCA content, clinical outcomes, progression of liver fibrosis, hepatobiliary cancer risk, liver transplantation, or overall survival.

Purpose Anemia is common among patients with colorectal cancer and is associated with an increased risk of complications and poorer survival rate. The main objective of our study was to determine the effect of preoperative intravenous iron supplementation therapy on the need for red blood cell transfusions, other postoperative complications, and length of hospital stay in colon cancer patients undergoing colon resection. Methods In this retrospective cohort study, data were collected from medical records of all 549 colon carcinoma patients who underwent a colon resection in Helsinki University Hospital during the years 2017 and 2018. The patients were divided into two cohorts: one with anemic patients treated with preoperative intravenous iron supplementation therapy (180 patients) and one with anemic patients without preoperative intravenous iron supplementation therapy (138 patients). Non-anemic patients and patients requiring emergency surgery were excluded (231 patients). Results Patients treated with intravenous iron had less postoperative complications (33.9% vs. 45.9%, p = 0.045) and a lower prevalence of anemia at 1 month after surgery (38.7% vs. 65.3%, p Conclusion This is the first study demonstrating a significant decrease in postoperative complications in anemic colon cancer patients receiving preoperative intravenous iron supplementation therapy. This treatment also diminishes the rate of postoperative anemia, which is often associated with a facilitated recovery.

Background: Cholangiocarcinoma (CCA) is a cancer arising from the intra- and extrahepatic bile ducts. The early stages are often asymptomatic, CCA is frequently diagnosed in an advanced stage and the prognosis of CCA is often dismal. Objective: Our objective was to estimate the incidence of CCA in Finland and to identify risk factors for CCA, with a special interest in primary sclerosing cholangitis (PSC). Methods: We identified all CCA cases during 1974–2018 from the Finnish Cancer Registry and calculated age-standardised incidence rates. Five controls for each case were extracted from the Population Registry, matched by age, gender and municipality of residence at the time of diagnosis. Odds ratios (ORs) for risk factors were estimated with conditional logistic regression and survival estimates with the Kaplan–Meier method. Results: Incidence of CCA remained stable in both genders; the age-standardised rate (World Standard) in 2013–2017 in males and females was 1.7 per 100,000 person years and 1.3 per 100,000 person years, respectively. Primary sclerosing cholangitis carried a 30-fold risk of intrahepatic cholangiocarcinoma (iCCA) and 25-fold risk of extrahepatic cholangiocarcinoma (eCCA). Diabetes, inflammatory bowel disease and liver cirrhosis were associated with iCCA, whereas cholelithiasis and viral hepatitis C were associated with eCCA. The cumulative 5-year survival was 4.6%. Conclusions: The incidence of CCA has been stable. Known risk factors for CCA were confirmed, with PSC having the highest OR. Survival remains poor. publishedVersion

Background & Aims Non-alcoholic fatty liver disease (NAFLD) increases morbidity and mortality. However, patients in biopsy-based cohorts are highly selected and the absolute risks of liver- and non-liver outcomes in NAFLD in population remains undefined. We analysed both liver-related and non-liver-related outcomes in Finnish population cohorts of NAFLD. Methods We included 10 993 individuals (6707 men, mean age 53.3 +/- 12.6 years) with NAFLD (fatty liver index >= 60) from the Finnish population-based FINRISK and Health 2000 studies. Liver fibrosis was assessed by the dAAR score, and genetic risk by a recent polygenic risk score (PRS-5). Incident liver-related outcomes, cardiovascular disease (CVD), cancer and chronic kidney disease (CKD) were identified through linkage with national registries. Results Mean follow-up was 12.1 years (1128 069 person-years). The crude incidence rate of liver-related outcomes in NAFLD was 0.97/1000 person-years. The cumulative incidence increased with age, being respectively 2.4% and 1.5% at 20 years in men and women aged 60 years at baseline, while the relative risks for CVD and cancer were 9-16 times higher. The risk of CKD exceeded that of liver outcomes at a baseline age around 50 years. 20-year cumulative incidence of liver-related outcomes was 4.3% in the high, and 1.5% in the low PRS-5 group. The dAAR score associated with liver outcomes, but not with extra-hepatic outcomes. Conclusion The absolute risk of liver-related outcomes in NAFLD is low, with much higher risk of CVD and cancer, emphasizing the need for more individualized and holistic risk-stratification in NAFLD.

Background The Ulcerative Colitis (UC) Narrative is a global patient and physician survey aimed at identifying the impact of UC and comparing and contrasting perceptions of UC burden and management approaches. Methods Surveys of patients with UC (self-reported diagnosis; n = 2100) and physicians (n = 1254) were completed across 10 countries by The Harris Poll between August 2017 and February 2018. Questionnaires covered multiple aspects of UC, including diagnosis, treatment, and impact on patient quality of life, in addition to standard demographic information. Descriptive statistics are reported. Results The majority of patients (82%) had moderate to severe UC (based on medication history; those who had only ever taken 5-aminosalicylates were excluded); 67% described their UC as controlled with few to no symptoms. On average, patients experienced 4.3 flares (standard deviation, 7.4) in the past year. Diagnostic delay was on average 2.0 years (standard deviation, 5.4); 42% of patients waited ≥1 year. Most patients (65%) felt that UC controlled their life rather than them controlling their disease. Because of the fear of repercussions, many patients had not disclosed their UC to their employer. Discussion of the emotional impact of UC during routine appointments was less of a priority for physicians, compared with patients. Conclusions The data from this global survey highlight that patients with UC experience diagnostic delay, poor disease control, and adverse impact on their quality of life. Patients report UC to be a mentally exhausting condition; however, emotional and mental health issues are infrequently discussed at routine appointments., Graphical Abstract

Background Difficult biliary cannulation in endoscopic retrograde cholangiopancreatography (ERCP) increases the risk of post-ERCP pancreatitis (PEP). The purpose of this prospective, randomized, multicenter study was to compare two advanced rescue methods, transpancreatic biliary sphincterotomy (TPBS) and a double-guidewire (DGW) technique, in difficult common bile duct (CBD) cannulation. Methods Patients with native papilla and planned CBD cannulation were recruited at eight Scandinavian hospitals. An experienced endoscopist attempted CBD cannulation with wire-guided cannulation. If the procedure fulfilled the definition of difficult cannulation and a guidewire entered the pancreatic duct, randomization to either TPBS or to DGW was performed. If the randomized method failed, any method available was performed. The primary end point was the frequency of PEP and the secondary end points included successful cannulation with the randomized method. Results In total, 1190 patients were recruited and 203 (17.1 %) were randomized according to the study protocol (TPBS 104 and DGW 99). PEP developed in 14/104 patients (13.5 %) in the TPBS group and 16/99 patients (16.2 %) in the DGW group (P = 0.69). No difference existed in PEP severity between the groups. The rate of successful deep biliary cannulation was significantly higher with TPBS (84.6 % [88/104]) than with DGW (69.7 % [69/99]; P = 0.01). Conclusions In difficult biliary cannulation, there was no difference in PEP rate between TPBS and DGW techniques. TPBS is a good alternative in cases of difficult cannulation when the guidewire is in the pancreatic duct.

BACKGROUND & AIMS While several anthropometric measures predict liver disease, the waist-hip ratio (WHR) has shown superiority in previous studies. We analysed independent and joint associations of waist circumference (WC) and hip circumference (HC) with liver disease and liver-related risk factors. METHODS Cross-sectional study (n = 6619) and longitudinal cohort (n = 40 923) comprised individuals from Health 2000 and FINRISK 1992-2012 studies. Prevalent and viral liver diseases were excluded. Longitudinal cohort was linked with national healthcare registers for severe incident liver disease. Linear regression and Cox proportional hazards models were used to analyse anthropometric, lifestyle, metabolic and bioimpedance-related parameters; liver enzymes; and 59 liver-related genetic risk variants. RESULTS WC and HC showed independent and opposite associations with both liver enzymes and incident liver disease among men (HR for liver disease: WC, 1.07, 95% CI 1.03-1.11; HC, 0.96, 95% CI 0.92-0.99; P-range .04 to

Introduction: Risk of post-ERC pancreatitis (PEP) in patients with primary sclerosing cholangitis (PSC) is 1-7.8%. PSC is often associated with inflammatory bowel disease and autoimmune hepatitis, which are usually treated with thiopurines. The role of thiopurines in PEP risk is still unclear. Aims and methods: We evaluated the thiopurine use in PEP. The data of 354 PSC patients who underwent 985 ERCs between 2009 and 2018 were collected. 177 patients treated with thiopurines (study group, SG) and 177 controls (CG) were matched with a propensity score (PSM). Odds ratios (ORs) with 95% confidence interval (95% CI) were calculated. Multivariable logistic regression analysis and generalized linear mixed model were performed. The P-value < 0.05 was significant. Results: In matched data, 472 ERCs were performed in SG and 513 in CG. Thiopurines were used in 373/472 (79.0%) ERCs in SG. The PEP rate was 5.3% in SG and 5.7% in CG ( p = 0.889). Unintentional pancreatic duct cannulation (OR 1.28, 95%CI 1.07-1.51, p = 0.004), and periampullary diverticulum (OR 4.87, 95%CI 1.72-11.98, p = 0.001) increased the risk of PEP. Conclusion: Prior or present thiopurine use did not increase the risk of PEP. (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Background & Aims Gut-derived endotoxemia has been implicated in the development of chronic liver disease, but its relevance at the population level remains unclear. We analyzed whether endotoxemia is associated with incident advanced liver disease in the general population. Methods Serum lipopolysaccharide (LPS) was measured in 6,727 (3,455 male and 3,272 female, mean age 53.4 ± 10.9 years, mean body mass index 27.2 ± 4.5) individuals participating in the Finnish population-based health examination survey FINRISK 1997. Data were linked with electronic health registers for incident advanced liver disease (hospitalization, cancer or death related to liver disease). During a mean follow-up of 16.3 ± 3.8 years (109,282 person-years), 86 liver events occurred. Univariate and multivariate Cox regression, and Kaplan-Meier analyses were performed. Results Serum LPS predicted incident advanced liver disease with a hazard ratio per 1 SD of 1.41 (95% CI 1.24–1.59; p ≪0.001) when adjusted for age, sex, gamma-glutamyltransferase, metabolic syndrome, alcohol use, patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M, waist-hip ratio and type 2 diabetes. This association remained robustly significant in additional multivariate analyses with various levels of adjustment. The association was accentuated among carriers of the PNPLA3 risk variant. The population attributable fraction of the highest LPS tertile for liver events was 29.7%. However, LPS was not associated with all-cause mortality. Conclusion Serum LPS is associated with hospitalization, cancer or death related to liver disease in the general population, with the highest tertile potentially accounting for 30% of the risk of liver disease. Lay summary Lipopolysaccharide, a gut-derived bacterial endotoxin, has been implicated in the development of chronic liver disease, but its relevance at the population level remains unclear. We found that serum lipopolysaccharide levels were associated with incident advanced liver disease in the general population, with the highest tertile accounting for up to 30% of the risk of hospitalization, cancer or death related to liver disease., Graphical abstract Unlabelled Image, Highlights • Serum LPS was associated with incident advanced liver disease in the general population. • LPS was associated with liver-related risk of hospitalization, cancer or death. • The highest LPS tertile may account for up to 30% of the risk of incident liver disease. • The risk of liver disease was accentuated among carriers of the PNPLA3 I143M. • Serum LPS was not associated with all-cause mortality.

Background and Aim Liver disease is traditionally categorized as alcoholic and non-alcoholic. We studied various risk factors predictive of advanced non-viral liver disease in general population and analyzed the interaction between these factors and alcohol consumption. Methods Persons without underlying liver disease who participated in the Health2000 or FINRISK studies 1992-2012 comprised a cohort of 41 260 individuals. Pattern of alcohol consumption and metabolic, lifestyle-related, and anthropometric parameters were analyzed with Cox regression analysis using severe liver disease hospitalization, cancer, or death as end-point. Viral liver diseases were excluded. Results A total of 355 liver events occurred during the mean 12.4-year follow-up (511 789 person-years). In the multivariate model, age (hazard ratio [HR] 1.03, P = 0.0083 for men; HR 1.04, P = 0.0198 for women), waist-to-hip ratio (WHR) (HR 1.52, P = 0.0006 for men; HR 1.58, P = 0.0167 for women), patatin-like phospholipase-containing domain 3 mutations (HR 1.9, P = 0.024 for men; HR 2.7, P = 0.0109 for women), and weekly binge drinking (HR 2.4, P = 0.0024 for men; HR 7.4, P

Objectives: Parenteral support (PS) is the first-line therapy for intestinal failure (IF). Optimal patient outcomes require experienced multidisciplinary teams adhering to structured protocols. As practices to provide long-term PS for adult IF patients in Finland are unknown, this cross-sectional nationwide study aimed to evaluate current management of PS for adult IF across the country.Materials and methods: An internet-based survey was emailed to all Finnish hospitals and hospital-at-home services with the potential to provide PS for adult IF. The survey included 20 items addressing the provision of long-term PS for adult IF patients (aged >= 18years). Data were analysed using descriptive statistics.Results: Overall, 52 (47%) of the 111 identified units responded. Of responding units, 38 (73%) had at some point provided long-term (>= 120days) PS for adult IF, and 23 (44%) had done so during the preceding year. Only three units currently managed >= 3 adult patients. Most (65%) of the respondents worked in a hospital and were either physicians (38%) or dietitians (39%). Only 65% of respondents reported that their unit had an assigned physician responsible for PS provision, and 28% reported that a team was responsible for long-term PS. Only 26% of respondents reported having a written protocol to guide PS management.Conclusions: Health care providers with very limited experience and a fragmented approach manage most Finnish adult IF patients. Evidence-based protocols and multidisciplinary teams are scarce. The care for adult IF patients on long-term PS needs to be improved in Finland.

Trypsin has been identified as a pancreatic protease comprising three isoenzymes, trypsin-1,-2, and-3. However, the gene for trypsinogen-3, PRSS3, also gives rise to additional variants, trypsinogen-4A and B, which differ from trypsinogen-3 only with respect to the leader-peptide part, and when activated are identical to trypsin-3. The unique overlapping leader peptides of trypsinogen-4A and B allowed us to develop a specific sandwich-type immunofluorometric assay that detects both these isoforms, but not trypsinogen-3 or activated trypsinogen-4. We measured the concentrations of trypsinogen-4 in various cell line lysates and bile of primary sclerosing cholangitis patients. Lysates of cell lines MDA-MB-231 and PC-3, and astrocytes contained trypsinogen-4, while the conditioned media from these cells did not, suggesting that trypsinogen-4, lacking a classical signal sequence, is not secreted from the cells. Interestingly, 5.7% of the 212 bile samples analyzed contained measurable (>2.4 mu g/l) trypsinogen-4. In conclusion, we have established a specific assay for trypsinogen-4 and demonstrated that trypsinogen-4 can be found in biological samples. However, the clinical utility of the assay remains to be established.

Tulehdukselliset suolistosairaudet (IBD) Crohnin tauti (CD) ja haavainen paksusuolentulehdus (UC) ovat maailmanlaajuisesti lisääntyviä sairauksia, joihin liittyy muuntunut suoliston mikrobisto. Infliksimabi (IFX) on TNF-alfan estäjä, jota käytetään IBD:n hoidossa, vaikkakin kolmas osa potilaista voi jäädä ilman hoitovastetta tai menettää sen. Luotettavia testejä hoitovasteen ennustamiseksi ei ole vielä saatavilla. Tutkimuksemme tavoitteena oli selvittää potilaiden ulosteen bakteerit, sienet ja hiivat infliksimabihoidon aikana sekä etsiä hoitovastetta ennustavia mittareita IBD potilailta. Tutkimuksessamme 72 IBD-potilasta (25 CD ja 47 UC) aloitti infliksimabihoidon ja heitä seurattiin vuoden ajan hoidon aloituksesta tai hoidon keskeytykseen saakka. Potilaiden ulostenäytteistä määritettiin sekvensointia hyödyntäen erikseen suoliston bakteerit (16S rRNA geenistä) sekä hiivat ja sienet (ITS1 geenin alueesta). Mikrobiston profiilit määritettiin ennen hoidon aloitusta, 2, 6, 12 viikkoa sekä 1 vuosi hoidon aloituksen jälkeen. IFX hoidon vaste määritettiin kolonoskopialla ja kliinisesti 12 viikon hoidon jälkeen. Tutkimuksessa havaittiin, että potilaiden ulosteen bakteerit sekä sienet ja hiivat erosivat merkittävästi toisistaan infliksimabihoitovasteen mukaan jo ennen hoidon aloitusta. Potilailla, jotka eivät saaneet vastetta hoidosta, oli vähemmän lyhytketjuisia rasvahappoja tuottavia bakteereja erityisesti Clostridia-luokasta sekä enemmän tulehdusta aiheuttavia bakteereja ja sieniä mm. Candida-suvusta. Tämä tulos testattiin bakteerien osalta myös ennustetestillä (ROC), joka erotti toisistaan ne potilaat, jotka saivat hyvän vasteen ja ne, jotka eivät saaneet vastetta (area under the curve > 0.8). Tulosten perusteella ulosteen bakteerit ja hiivat voisivat sopia ennustaviksi mittareiksi IBD-potilaiden infliksimabihoidon vasteen ennustamiseen.

Background Behavioral therapy (BT) has been proven effective in the treatment of supragastric belching (SGB) in open studies. The aim was to compare BT to follow-up without intervention in patients with SGB in a randomized study. Methods Forty-two patients were randomized to receive 5 sessions of BT, comprising diaphragmatic breathing exercises, or to follow-up without intervention. Patients were evaluated at 6 months, at which point the control group was also offered BT and evaluated after another 6 months. The frequency and intensity of belching and mental well-being were evaluated with a visual analog scale (VAS). Depression, anxiety, and health-related quality of life (HRQoL) were evaluated with four questionnaires: BDI, BAI, 15D, and RAND-36. Key results The frequency and intensity of SGB were significantly lower in the therapy group (n = 19) than in the control group (n = 18) at the 6-month control (p < 0.001). When all patients (n = 36) were evaluated 6 months after BT, in addition to relief in the frequency and intensity of belching (p < 0.001), mental well-being had also improved (p < 0.05). Of all 36 patients, 27(75%) responded to BT. Depression scores were lower after therapy (p < 0.05). Only minor changes occurred in anxiety and HRQoL. Conclusions and Inferences Behavioral therapy is superior to follow-up without intervention in patients with SGB in reducing belching and depression; it also improves mental well-being but has only a modest effect on anxiety and HRQoL.

Background The objective was to build a novel method for automated image analysis to locate and quantify the number of cytokeratin 7 (K7)-positive hepatocytes reflecting cholestasis by applying deep learning neural networks (AI model) in a cohort of 210 liver specimens. We aimed to study the correlation between the AI model’s results and disease progression. The cohort of liver biopsies which served as a model of chronic cholestatic liver disease comprised of patients diagnosed with primary sclerosing cholangitis (PSC). Methods In a cohort of patients with PSC identified from the PSC registry of the University Hospital of Helsinki, their K7-stained liver biopsy specimens were scored by a pathologist (human K7 score) and then digitally analyzed for K7-positive hepatocytes (K7%area). The digital analysis was by a K7-AI model created in an Aiforia Technologies cloud platform. For validation, values were human K7 score, stage of disease (Metavir and Nakunuma fibrosis score), and plasma liver enzymes indicating clinical cholestasis, all subjected to correlation analysis. Results The K7-AI model results (K7%area) correlated with the human K7 score (0.896; p

Background: Real-world evidence to support optimal ustekinumab dosing for refractory Crohn’s disease (CD) patients remains limited. Data from a retrospective nationwide chart review study was utilized to explore ustekinumab dosing dynamics and optimization, identify possible clinical predictors of dose intensification, and to evaluate ustekinumab trough concentrations (TCs) and concomitant medication use in Finland. Methods: Information gathered from17 Finnish hospitals included clinical chart data from 155 adult CD patients who received intravenous ustekinumab induction during 2017–2018. Data on ustekinumab dosing and TCs, concomitant corticosteroid and immunosuppressant use, and antiustekinumab antibodies were analyzed in a two-year follow-up, subject to availability. Results: Among 140 patients onustekinumab maintenance therapy, dose optimization was required in 55(39%) of the patients, and 41/47 dose-intensified patients (87%) persisted on ustekinumab. At baseline, dose-intensified patient group had significantly higher C-reactive protein (CRP) levels, and at week 16, significantly lower ustekinumab TCs than in patients without dose intensification. Irrespective of dose optimization, a statistically significant reduction in the use of corticosteroids was observed at both 16 weeks and one year, coupled with an increased proportion of patients on ustekinumab monotherapy. Antiustekinumab antibodies were undetectable in all 28 samples from 25 patients collected throughout the study period. Conclusions: Nearly a third of all CD patients on ustekinumab maintenance therapy, with a history of treatment-refractory and long-standing disease, required dose intensification. These patients persisted on ustekinumab and had significant reduction of corticosteroid use. Increased baseline CRP was identified as the sole indicator of dose intensification. Trial registration: EUPAS30920. publishedVersion

Introduction: The coronavirus disease 2019 (COVID-19) pandemic poses a challenge to healthcare. Staff and patients are at increased risk during an examination or intervention, so certain restrictions ought to be introduced. Hence, we aimed to measure the effect of the pandemic on endoscopy units in real-life settings. Methods: This was an observational, cross-sectional, questionnaire-based study, carried out between 7 April and 15 June 2020. Responds came from many countries, and the participation was voluntary. The survey contained 40 questions, which evaluated the effect of the COVID-19 pandemic on the endoscopy units and assessed the infection control. Results: A total of 312 questionnaires were filled, 120 from Hungary, and 192 internationally, and 54 questionnaires (17.3%) were sent from high-risk countries; 84.9% of the gastroenterologists declared that they read the European Society of Gastrointestinal Endoscopy (ESGE) statement, while only 32.1% participated in any advanced training at their workplace. Overall, 92.1% of gastroenterologists realized risk stratification, and 72.1% claimed to have enough protective equipment. In 52.6% of the endoscopy units, at least one endoscopist had to discontinue the work due to any risk factor, while 40.6% reported that the reduced staff did not affect the workflow. Gastroenterologists considered that the five most important examinations both in low and high-risk patients are the following: lower/upper gastrointestinal (GI) bleeding with hemodynamic instability, endoscopic retrograde cholangiopancreatography (ERCP) in obstructive jaundice, foreign body in the esophagus, ERCP in acute biliary pancreatitis, and iron deficiency anemia with hemodynamic instability, which correlates well with the ESGE recommendation. Significant correlation was found in the usage of the necessary protective equipment in high-risk patients depending on the countries ( p Conclusions: The survey found weak correlation in preliminary training depending on countries; nevertheless, in Hungary during the examined period, endoscopists considered the recommendations more strictly than in other countries. Although many physicians left the endoscopy lab, the workflow was not affected, probably due to the reduced number of examinations.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a rare bile duct disease strongly associated with inflammatory bowel disease (IBD). Whole-exome sequencing (WES) has contributed to understanding the molecular basis of very early-onset IBD, but rare protein-altering genetic variants have not been identified for early-onset PSC. We performed WES in patients diagnosed with PSC ≤ 12 years to investigate the contribution of rare genetic variants to early-onset PSC. METHODS: In this multicentre study, WES was performed on 87 DNA samples from 29 patient-parent trios with early-onset PSC. We selected rare (minor allele frequency

International audience; BACKGROUND/AIMS: Few data on the evolution of endoscopic findings are available in patients with acute severe ulcerative colitis (ASUC). The aim of this study was to describe this evolution in a prospective cohort. METHODS: Patients admitted for a steroid-refractory ASUC and included in a randomized trial comparing infliximab and cyclosporine were eligible if they achieved steroid-free clinical remission at day 98. Flexible sigmoidoscopies were performed at baseline, days 7, 42 and 98. Ulcerative colitis endoscopic index of severity (UCEIS) and its sub-scores - vascular pattern, bleeding and ulceration/erosion - were post-hoc calculated. Global endoscopic remission was defined by a UCEIS of 0, and partial endoscopic remission by any UCEIS sub-score of 0. RESULTS: Among the 55 patients analyzed (29 infliximab and 26 cyclosporine), 49 (83%) had UCEIS >= 6 at baseline at baseline. Partial endoscopic remission rates were higher for bleeding than for vascular pattern and for ulcerations/erosions at day 7 (20% vs. 4% and 5% (n = 55); p

Vertaisarvioitu. English summary. • Tulehduksellisten suolistosairauksien hoito on kehittynyt merkittävästi viime vuosikymmeninä, mutta silti sairauteen ei ole parantavaa hoitoa. • Uudet lääkevaihtoehdot ovat muuttaneet hoidon aiempaa yksilöllisemmäksi. • Sairaanhoitopiirien laatimien hoitoketjujen mukaisesti rauhallisessa vaiheessa taudin seuranta voidaan toteuttaa perusterveydenhuollossa erikoissaanhoidosta saatujen ohjeiden mukaisesti.

Objectives We set out to determine the reasons for serum vedolizumab (VDZ) trough concentration (TC) measurements in inflammatory bowel disease (IBD) patients and to evaluate treatment modifications after therapeutic drug measurement (TDM). We also evaluated the effect of increased dosing on patients' response to VDZ therapy. Methods We performed a retrospective cohort study of IBD patients who received VDZ therapy at Helsinki University Hospital and whose VDZ levels were measured between June 2014 and December 2018. Results Altogether, 90 patients (32 Crohn's disease and 58 ulcerative colitis) and 141 VDZ TC measurements were included. 24.1% of measurements took place during induction and 75.9% during the maintenance phase. During induction, 64.7% reached the target TC >20 mu g/ml. During maintenance therapy, 82.2% of VDZ TCs were within or exceeded the suggested target range of 5-15 mu g/ml. Reasons for TDM were: secondary nonresponse (44.0%), assessment of adequate VDZ TC (25.5%), primary nonresponse (12.8%), adverse events (6.4%), and other (11.3%). No treatment changes occurred after 60.3% of VDZ measurements. Increased dose frequency was used after 25.5% of VDZ measurements and 33.3% of these patients experienced improvement. Altogether, 31 (34.4%) patients discontinued the therapy due to inadequate treatment response. No anti-vedolizumab antibodies were detected. Conclusions During the maintenance of VDZ therapy, the majority of VDZ TCs were within the suggested range. Measurement of VDZ TC did not lead to any treatment changes in two-thirds of patients. Dose optimization occurred in a quarter of patients and a third of them benefited from it.

Background: Multiple studies have described the effectiveness of ustekinumab (UST) and vedolizumab (VDZ) in patients with Crohn’s disease (CD) failing anti- Tumor necrosis factors (TNFs), however, the effectiveness of VDZ or UST as a third-class biologic has not yet been described. Aims and Methods: In this retrospective multicenter cohort study, we aimed to investigate the effectiveness of VDZ and UST as a third-class biologic in patients with CD. Results: Two-hundred and four patients were included, 156/204 (76%) patients received VDZ as a second- and UST as a third-class therapy (group A), the remaining 48/204 (24%) patients received UST as a second- and VDZ as a third-class therapy (group B). At week 16–22, 87/156 (55.5%) patients and 27/48 (56.2%) in groups A and B, respectively, responded to treatment (p = 0.9), 41/156 (26.2%) and 15/48 (31.2%) were in clinical remission (p = 0.5). At week 52, 89/103 (86%) patients and 25/29 (86.2%) of the patients with available data had responded to third-class treatment in groups A and B, respectively (p = 0.9), 31/103 (30%) and 47/29 (24.1%) were in clinical remission (p = 0.5). Conclusion: Third-class biological therapy was effective in more than half of the patients with CD. No differences in effectiveness were detected between the use of VDZ and UST as a third-class agent.