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Purpose of review Primary sclerosing cholangitis (PSC) is a progressive biliary liver disorder strongly associated with inflammatory bowel disease (PSC-IBD). We summarize the genetics of PSC-IBD and highlight recent findings that further differentiate PSC-IBD as a unique disease. Recent findings To date, genome-wide studies have uncovered 23 susceptibility loci for PSC-IBD, the majority of which have been previously reported as risk factors in other immune-mediated disorders. For most candidates, the pathological relationship to PSC-IBD remains largely unknown. Several candidate genes appear to be liver related but the large majority relate to immunity and reaffirm that alterations to immune function, trafficking, and tolerance are likely to influence susceptibility and presentation of PSC-IBD. Similar to most immune-mediated diseases, the strongest association in PSC-IBD resides within the human leukocyte antigen complex and suggests that disease-specific antigens drive pathogenic immune responses. Although genetic predisposition influences disease, genetic determinants account for less than 10% of total disease liability in PSC-IBD, clearly emphasizing the predominant role of environmental factors on disease susceptibility. Summary Genetic studies define PSC-IBD as a unique disease to IBD mirroring clinical observations. Most risk loci harbour immune-related genes and disease variants are likely to perturb immune function, tolerance, and/or trafficking. Additional studies in patients and novel experimental systems are needed to identify the origin and impact of environmental factors in relation to genetic predisposition in PSC-IBD.

Background: Over the last 50 years, genetic studies have uncovered a spectrum of rare and common alleles that confer susceptibility to both Mendelian and complex forms of liver disease. For disorders of Mendelian inheritance, identification of the causal variants has demonstrated that common environmental exposures can elicit severe liver pathogenesis in predisposed individuals. Specific environmental triggers for complex liver disorders are largely unknown; however, large-scale association studies indicate that environmental triggers are the predominant factors in driving liver pathophysiology. Key Messages: In Mendelian liver disorders, a single rare variant of major effect is often responsible for disease development. Gene-sequencing technologies have greatly facilitated the discovery of causal variants for Mendelian diseases and are increasingly utilized in molecular and clinical genetics for diagnostic and counselling purposes. By contrast, genetic susceptibility for complex liver disorders is heterogeneous, as many different genes acting on multiple distinct pathways influence disease onset and severity. Risk variants for complex liver disorders are relatively common, typically of small effect size and detected by genome-wide association studies (GWAS), which compare the genetic variation of specific loci using thousands of patients and healthy controls. Thus far, GWAS have detected dozens of unique and overlapping risk alleles for complex liver disease, but these account for less than a quarter of the overall disease liability. These observations emphasize that environmental exposures on a background of genetic predisposition are significant drivers of liver pathophysiology. Rare variants of large effect size, undetectable by GWAS, may also affect the development of complex disease on a case-to-case basis but evidence for such a scenario remains to be determined. Conclusions: Genetic technologies have identified numerous risk genes for Mendelian and complex liver disorders transforming disease recognition. For complex liver disorders, deciphering the interplay between genetic risk and environment determinants remains a significant challenge for unlocking the development of novel and personalized interventions.

Background Systemic sclerosis (SSc) is a progressive, multi organ, auto-immune disease marked by frequent and severe gastrointestinal (GI) afflictions and gut dysbiosis. Objectives Determine the safety and efficacy of fecal microbiota transplantation (FMT) using commercially-available anaerobic cultivated human intestinal microbiota (ACHIM) in patients with SSc. Methods The trial was a single-center, randomized, double-blind, placebo-controlled 16-week pilot of FMT by gastroduodenoscopy of ACHIM in SSc conducted at Oslo University Hospital. Primary endpoints were safety and clinical efficacy on GI symptoms assessed at weeks 4 and 16. Safety was assessed by observation, interviews and standardized safety form. Efficacy on GI symptoms was measured using the UCLA GIT 2.0 score questionnaire. Patients were defined as responders if reported symptom improvement was equivalent to the UCLA GIT definition of “minimally clinically important difference”. Secondary and explorative endpoints included changes in relative abundance of total, immunoglobulin (Ig)A- and IgM-coated fecal bacteria measured by 16s rRNA sequencing; changes in modified Rodnan skin score, lung function, CRP, ESR, and patient and physician global. Descriptive statistics were applied for clinical endpoints and linear mixed models for microbial analysis. Results Ten patients with limited cutaneous SSc randomized to ACHIM (n=5) or placebo (n=5) were included. All patients were female with clinical apparent GI symptoms, mean age of 62 years and mean time from diagnosis of 12 yrs. Two placebo controls experienced procedure-related serious adverse events; one developed laryngospasms at first gastroduodenoscopy necessitating study exclusion, one duodenal perforation at final gastroduodenoscopy. Improvement in total GIT score was reported by 3/5 FMT patients compared to 2/4 placebo controls at weeks 4 and 16 (Figure 1). FMT effects were most pronounced on lower GI symptoms, with improvement reported by 5/5 FMT patients with diarrhea, distention/bloating and/or fecal incontinence at baseline compared to 2/4 placebo controls (Figure). Clinical secondary endpoints showed no differences and other side effects (stomach discomfort, bloating and diarrhea) were mild and transient. Fecal microbiota diversity (observed number of operational taxonomic units) was increased after FMT compared to placebo treatment at week 16 (p Conclusion FMT of commercially-available ACHIM in patients with SSc appeared safe, effectively reduced lower GI symptoms, altered gut microbiota composition, richness and diversity and appeared to affect the mucosal immune system Disclosure of Interests Anna-Maria Hoffmann-Vold Grant/research support from: Received research funding or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Consultant for: Received consulting fees or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Speakers bureau: Actelion and Boehringer Ingelheim, Havard Fretheim Consultant for: Received consulting fees or other remuneration from GSK, and Actelion, Brian K Chung: None declared, Henriette Didriksen Consultant for: Received consulting fees or other remuneration from GSK, and Actelion, Espen S Baekkevold: None declared, Oyvind Midtvedt: None declared, Cathrine Brunborg: None declared, Torhild Garen: None declared, Tore Midtvedt Shareholder of: Owner of ACHIM, Johannes R Hov: None declared, Knut EA Lundin: None declared, Oyvind Molberg: None declared

Background Despite recent advances in the diagnosis and understanding of many autoinflammatory diseases, there are still a great number of patients with phenotypes that do not fit any clinically- and/or genetically-defined disorders. Case presentation We describe a fourteen-year-old boy who presented at two and a half years of age with recurrent febrile episodes. Over the course of the disease, the episodes increased in frequency and severity, with new signs and symptoms continuing to appear. Most importantly, these included skin changes, splenomegaly and transaminitis. Only partial control of the disease was achieved with anti-IL-1 therapy. Extensive investigation showed generalized inflammation without immune deficiency, with increased levels of serum amyloid A and several pro-inflammatory cytokines including interferon-γ, as well as an increased type I interferon score. Exome sequence analysis identified P369S and R408Q variants in the MEFV innate immunity regulator, pyrin (MEFV) gene and T260 M and T320 M variants in the NLR family pyrin domain containing 12 (NLRP12) gene. Conclusion Patients with unclassified and/or unexplained autoinflammatory syndromes present diagnostic and therapeutic challenges and collectively form a substantial part of every cohort of patients with autoinflammatory diseases. Therefore, it is important to acquire their full genomic profile through whole exome and/or genome sequencing and present their cases to a broader audience, to facilitate characterization of similar patients. A critical mass of well-characterized cases will lead to improved diagnosis and informed treatment.

Objectives Systemic sclerosis (SSc) is an auto-immune, multi organ disease marked by severe gastrointestinal (GI) involvement and gut dysbiosis. Here, we aimed to determine the safety and efficacy of fecal microbiota transplantation (FMT) using commercially-available anaerobic cultivated human intestinal microbiota (ACHIM) in SSc. Methods Ten patients with SSc were randomized to ACHIM (n = 5) or placebo (n = 5) in a double-blind, placebo-controlled 16-week pilot. All patients had mild to severe upper and lower GI symptoms including diarrhea, distention/bloating and/or fecal incontinence at baseline. Gastroduodenoscopy transfer of ACHIM or placebo was performed at weeks 0 and 2. Primary endpoints were safety and clinical efficacy on GI symptoms assessed at weeks 4 and 16. Secondary endpoints included changes in relative abundance of total, immunoglobulin (Ig) A- and IgM-coated fecal bacteria measured by 16s rRNA sequencing. Results ACHIM side effects were mild and transient. Two placebo controls experienced procedure-related serious adverse events; one developed laryngospasms at week 0 gastroduodenoscopy necessitating study exclusion whilst one encountered duodenal perforation during gastroduodenoscopy at the last study visit (week 16). Decreased bloating, diarrhea and/or fecal incontinence was observed in four of five patients in the FMT group (week 4 or/and 16) and in two of four in the placebo group (week 4 or 16). Relative abundance, richness and diversity of total and IgA-coated and IgM-coated bacteria fluctuated more after FMT, than after placebo. Conclusions FMT of commercially-available ACHIM is associated with gastroduodenoscopy complications but reduces lower GI symptoms by possibly altering the gut microbiota in patients with SSc.

B cells express an antigen-specific B-cell receptor (BCR) and may contribute to liver inflammation by recognizing shared antigens in the gut and liver. Herein, we used high-throughput BCR sequencing of the immunoglobulin heavy chain, specifically the complementarity-determining region 3 (CDR3), to characterize the B-cell repertoire of freshly-frozen paired gut and liver tissue samples from patients with primary sclerosing cholangitis (PSC) and concurrent inflammatory bowel disease (IBD) (PSC-IBD, n = 10) and paired formalin-fixed paraffin-embedded (FFPE) tumor-adjacent normal colon and liver tissue from patients with colorectal liver metastases (controls, n = 10). We observed significantly greater numbers of B cells (P < 0.01) and unique B-cell clonotypes (P < 0.05) in gut samples compared to liver samples of patients with PSC-IBD, whereas BCR sequences in FFPE normal gut and liver samples were nearly absent (14 ± 5 clonotypes; mean ± SD; n = 20). In PSC-IBD, an average of 8.3% (range, 1.6%-18.0%) of B-cell clonotypes were found to overlap paired gut and liver samples following the exclusion of memory clonotypes reported in the blood of healthy controls. Overlapping gut and liver clonotypes showed stronger evidence of antigen-driven activation compared to non-overlapping clonotypes, including shorter CDR3 lengths and higher counts of somatic hypermutation (P < 0.0001). Conclusion: A proportion of gut and liver B cells originate from a common clonal origin (i.e., likely to recognize the same antigen) in patients with PSC which suggests B-cell antigens are shared across the gut-liver axis. (Hepatology Communications 2018; 00:000-000).

Primary sclerosing cholangitis (PSC) is an idiopathic cholangiopathy strongly associated with inflammatory bowel disease (IBD) and characterized by cholestasis, chronic immune infiltration and progressive fibrosis of the intrahepatic and extrahepatic bile ducts. PSC confers a high risk of cholangiocarcinoma (CCA) with PSC-CCA representing the leading cause of PSC-associated mortality. PSC-CCA is derived from cholangiocytes and associated progenitor cells - a heterogeneous group of dynamic epithelial cells lining the biliary tree that modulate the composition and volume of bile production by the liver. Infection, inflammation and cholestasis can trigger cholangiocyte activation leading to an increased expression of adhesion and antigen-presenting molecules as well as the release of various inflammatory and fibrogenic mediators. As a result, activated cholangiocytes engage in a myriad of cellular processes, including hepatocellular proliferation, apoptosis, angiogenesis and fibrosis. Cholangiocytes can also regulate the recruitment of immune cells, mesenchymal cells, and endothelial cells that participate in tissue repair and destruction in settings of persistent inflammation. In PSC, the role of cholangiocytes and the mechanisms governing their transformation to PSC-CCA are unclear however localization of disease suggests that cholangiocytes are a key target and potential regulator of hepatobiliary immunity, fibrogenesis and tumorigenesis. Herein, we summarize mechanisms of cholangiocyte activation in PSC and highlight new insights into disease pathways that may contribute to the development of PSC-CCA. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

ObjectiveWe sought to conduct a major objective of the CAEP Academic Section, an environmental scan of the academic emergency medicine programs across the 17 Canadian medical schools.MethodsWe developed an 84-question questionnaire, which was distributed to academic heads. The responses were validated by phone by the lead author to ensure that the questions were answered completely and consistently. Details of pediatric emergency medicine units were excluded from the scan.ResultsAt eight of 17 universities, emergency medicine has full departmental status and at two it has no official academic status. Canadian academic emergency medicine is practiced at 46 major teaching hospitals and 13 specialized pediatric hospitals. Another 69 Canadian hospital EDs regularly take clinical clerks and emergency medicine residents. There are 31 full professors of emergency medicine in Canada. Teaching programs are strong with clerkships offered at 16/17 universities, CCFP(EM) programs at 17/17, and RCPSC residency programs at 14/17. Fourteen sites have at least one physician with a Master’s degree in education. There are 55 clinical researchers with salary support at 13 universities. Sixteen sites have published peer-reviewed papers in the past five years, ranging from four to 235 per site. Annual budgets range from $200,000 to $5,900,000.ConclusionThis comprehensive review of academic activities in emergency medicine across Canada identifies areas of strengths as well as opportunities for improvement. CAEP and the Academic Section hope we can ultimately improve ED patient care by sharing best academic practices and becoming better teachers, educators, and researchers.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are immune-mediated biliary diseases that demonstrate prominent and restricted genetic association with human leukocyte antigen (HLA) alleles. In PBC, anti-mitochondrial antibodies (AMA) are specific and used as diagnostic biomarkers. PSC-relevant auto-antibodies remain controversial despite a distinct HLA association that mirrors archetypical auto-antigen driven disorders. Herein, we compared antibody-secreting B cells (ASCs) in PSC and PBC liver explants to determine if liver-infiltrating ASCs represent an opportune and novel source of disease-relevant auto-antibodies. Using enzymatic digestion and mechanical disruption, liver mononuclear cells (LIMCs) were isolated from fresh PSC and PBC explants and plasmablast (CD19+CD27+CD38hiCD138−) and plasma cell (CD19+CD27+CD38hiCD138+) ASCs were enumerated by flow cytometry. We observed 45-fold fewer plasma cells in PSC explants (n = 9) compared to PBC samples (n = 5, p

Background & Aims Recruitment of gut-derived memory T-cells to the liver is believed to drive hepatic inflammation in primary sclerosing cholangitis (PSC). However, whether gut-infiltrating and liver-infiltrating T-cells share T cell receptors (TCRs) and antigenic specificities is unknown. We used paired gut and liver samples from PSC patients with concurrent inflammatory bowel disease (PSC-IBD), and normal tissue samples from colon cancer controls, to assess potential T cell clonotype overlap between the two compartments. Methods High-throughput sequencing of TCRβ repertoires was applied on matched colon, liver and blood samples from patients with PSC-IBD (n=10), and on paired tumor-adjacent normal gut and liver tissue samples from colon cancer patients (n=10). Results An average of 9.7% (range: 4.7–19.9%) memory T cell clonotypes overlapped in paired PSC-IBD affected gut and liver samples, after excluding clonotypes present at similar frequencies in blood. Shared clonotypes constituted on average 16.0% (range: 8.7–32.6%) and 15.0% (range: 5.9–26.3%) of the liver and gut memory T-cells, respectively. A significantly higher overlap was observed between paired PSC-IBD affected samples (8.7%, p =0.0007) compared to paired normal gut and liver samples (3.6%), after downsampling to equal number of reads. Conclusion Memory T-cells of common clonal origin were detected in paired gut and liver samples of patients with PSC-IBD. Our data indicate that this is related to PSC-IBD pathogenesis, suggesting that memory T-cells driven by shared antigens are present in the gut and liver of PSC-IBD patients. Our findings support efforts to therapeutically target memory T cell recruitment in PSC-IBD. Lay summary Primary sclerosing cholangitis (PSC) is a devastating liver disease strongly associated with inflammatory bowel disease (IBD). The cause of PSC is unknown, but it has been suggested that the immune reactions in the gut and the liver are connected. Our data demonstrate for the first time that a proportion of the T-cells in the gut and the liver react to similar triggers, and that this proportion is particularly high in patients with PSC and IBD.

ObjectivesEmergency physicians who work in academic settings enjoy an expanding number of roles beyond that of the skilled clinician. Faculty development (FD) encompasses the broad range of activities that institutions use to renew skill-sets and assist faculty members in these multiple roles. This study seeks to define the current FD needs and interests of Canadian academic emergency physicians (AEPs).MethodsAn online survey was administered to 943 AEPs in eight centers across Canada to determine their current FD activities, provide a detailed understanding of their FD needs and interests, elucidate the perceived barriers to and motivation for engaging in FD, and identify preferred methods of delivery for FD activities.ResultsThis national, cross-sectional survey was completed by 336 respondents. It shows that need for FD is universally high, particularly in traditional domains of scholarship, leadership and education (79%, 80%, 87% overall interest, respectively). However, the study also suggests that there is increasing need for FD in areas where current participation is lowest, namely research and social accountability (12% and 13% more interest, respectively). Senior and junior faculty evince equivalent overall FD interest (p>0.05), whereas female AEPs expressed greater overall FD needs in leadership (1.82 vs 1.44 activities, p=0.003) than males. Continued participation in FD activities is best promoted by offering relevant topics, at convenient times and locations.ConclusionsThis study reports the first comprehensive national FD needs assessment of Canadian academic emergency physicians.