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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 biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) have collectively been recognized as autoimmune liver diseases. They have all been subjected to genome-wide association studies (GWAS) and several dozens susceptibility loci have been determined. The predominant feature of the genetic findings is that of a strong association with the human leukocyte antigen (HLA) and numerous weak associations scattered throughout the remainder of the genome. The non-HLA associations show some degree of overlap, not only between PBC, PSC and AIH, but also with other autoimmune and immune-mediated diseases. Mathematical modelling shows that the main fraction of autoimmune disease risk (including that of autoimmune liver diseases) is not explained by GWAS, proposing a major role of environmental factors. The HLA associations and autoantibodies observed in these conditions may hold clues as to the nature of such factors, which are exceedingly difficult to map by means of epidemiological study designs. The present review article explores the potential relationship between genetic risk as determined by GWAS and environmental risk in autoimmune liver diseases, and proposes a model for relevant thinking on the susceptibility genes in PBC, PSC and AIH.

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.

Royal College of Physicians and Surgeons (RCPS) emergency medicine (EM) residents must complete a scholarly project; however, significant variation exists in Canadian EM resident research education and facilitation. We developed and implemented a novel mandatory research education rotation for RCPS EM residents intended to increase knowledge, faculty/resident collaborations, and, ultimately, scholarly output. This 4-week rotation took place in the fall of 2011 and consisted of 37 faculty-led didactic, critical appraisal, and workshop seminars. Exposure to faculty research and resulting opportunities and the development of resident research projects were integrated into the rotation. Twelve participating residents completed daily evaluations and took part in an exit focus group analyzed using a constant comparative method. Knowledge acquisition was assessed with a pre/post comprehensive examination instrument evaluated by a pairedt-test. Evaluations indicated generally high satisfaction throughout the rotation. Focus group analysis indicated that residents felt two important but competing goals existed: developing a research project and developing critical appraisal skills. The research knowledge of all participants improved significantly (mean/SD examination change +35.4%/+10.4%, range +20.0% to +53.6%,p< 0.001), and several new resident/faculty research collaborations arose from the rotation. A rotation of this nature is an efficient and effective means to increase research and critical appraisal knowledge and faculty/resident collaborations. As a result of our positive experience, the rotation will continue annually and has been expanded to include pediatric EM fellows. Longitudinal tracking of the participating trainee cohort will remain ongoing to assess the scholarly output impact of the rotation.

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.

SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs∗18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657∗]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway.