Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.

Construction and benchmarking of a multi-ethnic reference panel for the imputation of HLA class I and II alleles.

Genotype imputation of the human leukocyte antigen (HLA) region is a cost-effective means to infer classical HLA alleles from inexpensive and dense SNP array data. In the research setting, imputation helps avoid costs for wet lab-based HLA typing and thus renders association analyses of the HLA in large cohorts feasible. Yet, most HLA imputation reference panels target Caucasian ethnicities and multi-ethnic panels are scarce. We compiled a high-quality multi-ethnic reference panel based on genotypes measured with Illumina's Immunochip genotyping array and HLA types established using a high-resolution next generation sequencing approach. Our reference panel includes more than 1,300 samples from Germany, Malta, China, India, Iran, Japan and Korea and samples of African American ancestry for all classical HLA class I and II alleles including HLA-DRB3/4/5. Applying extensive cross-validation, we benchmarked the imputation using the HLA imputation tool HIBAG, our multi-ethnic reference and an independent, previously published data set compiled of subpopulations of the 1000 Genomes project. We achieved average imputation accuracies higher than 0.924 for the commonly studied HLA-A, -B, -C, -DQB1 and -DRB1 genes across all ethnicities. We investigated allele-specific imputation challenges in regard to geographic origin of the samples using sensitivity and specificity measurements as well as allele frequencies and identified HLA alleles that are challenging to impute for each of the populations separately. In conclusion, our new multi-ethnic reference data set allows for high resolution HLA imputation of genotypes at all classical HLA class I and II genes including the HLA-DRB3/4/5 loci based on diverse ancestry populations.

Vitamin D and Ulcerative Colitis: Is There a Relationship with Disease Extent?

INTRODUCTION: Patients with ulcerative colitis (UC) can suffer from low serum vitamin D that can result in complications such as low bone mineral density. It can also reflect underlying disease severity. METHODS: One hundred and ninety-seven patients previously diagnosed with UC from 2 European centers were prospectively recruited through the out-patient clinics. Clinical features (Montreal Classification, age, gender, previous and current medications, surgery), disease activity (Simple Clinical Colitis Activity Index [SCCAI]), blood investigations including serum inflammatory markers, and serum vitamin D were analyzed. The vitamin D levels were compared to a group of age- and gender-matched healthy controls. RESULTS: Mean vitamin D levels were lower in patients with UC (54.6 nmol/L) than in controls (80.7 nmol/L; p = 0.0001). Mean vitamin D levels was lowest in patients with extensive UC (E3; p = 0.0001). Serum vitamin D was not significantly different across treatment groups (p = 0.876). There was no statistical difference in vitamin D levels across patients receiving calcium and vitamin D supplements (p = 0.35) and there was no statistical correlation with SCCAI (p = 0.22). CONCLUSIONS: This study confirms the existence of low serum vitamin D in patients with UC when compared to healthy controls. It also provides evidence of an existing relationship between disease extent and serum vitamin D.

An unusual diverticulum adjacent to two large colonic polyps; a case report.

BACKGROUND: Adenocarcinomas can arise in a variety of circumstances in which intestinal segments have been used for urinary diversions. Whereas ureterosigmoidostomy is the oldest and simplest form of continent urinary diversion it also seems to be the most dangerous in this regard. Herein we present a case of colonic neoplasia complicating a non-functioning ureterosigmoidostomy after 55 years; the longest latent period documented to date. CASE PRESENTATION: A 56-year-old lady born with congenital bladder exystrophy and who had a functional ileal conduit presented to us with a 6 month history of change in bowel habit and rectal bleeding. Prior to this she had had multiple abdominal surgeries as a child and had suffered from lifelong recurrent urinary tract infections. Colonoscopy revealed the presence of two large sessile polyps in close proximity to a diverticulum-like structure that after surgical resection turned out to be a non-functioning ureterosigmoidostomy from when she was an infant. CONCLUSIONS: Our case highlights the importance of enrolling patients with ureterosigmoidostomies into long-term colonoscopic surveillance programmes. This is also true for those patients who undergo revisional surgery but have preserved ureteric stumps. Endoscopists should be aware of the varied endoscopic appearances of the anastamosis in order to be able to recognise these structures when present.

Corrigendum: The Conversion of Planned Colonoscopy to Sigmoidoscopy and the Effect of this Practice on the Measurement of Quality Indicators.

This corrects the article DOI: 10.1038/ajg.2017.138.

The Conversion of Planned Colonoscopy to Sigmoidoscopy and the Effect of this Practice on the Measurement of Quality Indicators.

OBJECTIVES: A cecal intubation rate (CIR) of >90% is a well-accepted quality indicator of colonoscopy and is consequently monitored within endoscopy units. Endoscopists' desire to meet this target may mean that incomplete colonoscopies are recorded as flexible sigmoidoscopies. The aim of this study was to examine whether the conversion of requested colonoscopies is a clinically significant phenomenon and whether this impacts upon the measurement of quality indicators. METHODS: A retrospective review of all flexible sigmoidoscopies performed between 1 January 2015 and 31 December 2015 at Nottingham University Hospitals, Sheffield Teaching Hospitals, and Cambridge University Hospitals was performed. Where a colonoscopy was requested but a flexible sigmoidoscopy performed, the patient's records and endoscopy reports were reviewed to determine whether this conversion was decided before the start of the procedure and documented. RESULTS: During the 12-month period, 6,839 flexible sigmoidoscopies were performed by 125 endoscopists. The original requests of 149 sigmoidoscopies could not be retrieved and were therefore excluded from this analysis. Of the 6,690 sigmoidoscopy requests reviewed, 2.8% (n=190) procedures were originally requested as a colonoscopy. On review of patient records, 85 conversions were appropriate according to pre-defined criteria. However, 105 conversions were deemed inappropriate, occurring in patients who had a valid documented indication for colonoscopy and had undergone full bowel preparation. The most common reasons cited included poor bowel preparation (n=37), technically challenging procedure (n=24), at the endoscopist's discretion based on clinical factors (n=21), and obstructing patology (n=8). A clear reason for conversion was not apparent in 11 cases. During the study period, 21,271 colonoscopies were performed and so conversions represent 0.45% of the total requests. When inappropriate conversions were included in individuals' performance data, 15 endoscopists fell to ≤90% target cecal intubation target. CONCLUSIONS: A small, but significant number of colonoscopies are converted to flexible sigmoidoscopies at the time of the procedure. This study demonstrates the conversion of colonoscopy to sigmoidoscopy as being a potential limitation of relying on CIR alone. Endoscopy units should consider monitoring the rate of inappropriate conversions to ensure quality.

Post-inflammatory Polyp Burden as a Prognostic Marker of Disease-outcome in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Post-inflammatory polyps [PIPs] are considered as indicators of previous episodes of severe inflammation and mucosal ulceration. Inflammatory bowel disease [IBD], namely Crohn's disease [CD] and ulcerative colitis [UC], exhibit a perpetuating, relapsing and remitting pattern, and PIPs are a frequent sequela of chronicity. The aim of this study was to determine whether a high PIP burden is associated with a more severe disease course in patients with IBD. METHODS: This was a multinational, multicentre, retrospective study. IBD patients previously diagnosed with PIPs were retrieved from the endoscopic database of each centre. PIP burden was evaluated and associated with demographic and clinical data as well as factors indicating a more unfavourable disease course. RESULTS: A total of 504 IBD patients with PIPs were recruited [male: 61.9%]. The mean age at IBD diagnosis was 36.9 [±16.8] years. Most patients [74.8%] were diagnosed with UC. A high PIP burden was present in 53.4% of patients. On multivariable Cox regression analysis, a high PIP burden was independently associated with treatment escalation (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.04-1.75; p = 0.024), hospitalization [HR 1.90; 95% CI 1.24-2.90; p = 0.003], need for surgery [HR 2.28; 95% CI 1.17-4.44, p = 0.02] and younger age at diagnosis [HR 0.99, 95% CI 0.98-0.99; p = 0.003]. CONCLUSION: PIP burden was associated with a more severe outcome. Future prospective studies should focus on the characterization of PIP burden as to further risk stratify this patient cohort.

Oesophagomediastinal fistula: a rare complication of tuberculosis.

We report a case of a woman from Thailand, living in Malta, who was diagnosed with concomitant tuberculosis (TB) and HIV with depleted CD4 count. Her case was further complicated by the formation of a fistula between the mediastinal lymph nodes and the oesophagus, an unusual finding but for which she had many risk factors. The diagnosis was suspected on CT scan of the thorax and confirmed via upper gastrointestinal endoscopy. Following the commencement of both anti-TB and antiretroviral therapy, she suffered a lapse of immune reconstitution inflammatory syndrome but with aggressive medical management eventually made a full recovery without the need for surgical intervention.

Identification of antibiotic resistance patterns in Helicobacter pylori strains isolated from gastric biopsies using real-time PCR and genotypic analysis.

BACKGROUND: Helicobacter pylori (H. pylori) is associated with dyspepsia, mucus-associated lymphoid tissue lymphoma, gastritis, and peptic ulcer disease. Treatment in Malta consists of triple therapy, which consists of a proton pump inhibitor and 2 of the antibiotics amoxicillin, clarithromycin, metronidazole and fluoroquinolones. We aimed to determine the resistance rates for clarithromycin and fluoroquinolones in patients with H. pylori, and its incidence, in patients undergoing an esophagogastroduodenoscopy (EGD) using real-time polymerase chain reaction (RT-PCR). METHODS: Patients undergoing an EGD were recruited. A rapid urease test (RUT) was performed, and 4 gastric biopsies were also taken (2 from antrum, 2 from corpus) and analyzed using RT-PCR. Positive samples were tested for antibiotic resistance using amplification and reverse hybridization techniques. RESULTS: Two hundred patients (mean age 53.6 [range 20-92] years; 53.1% female) were recruited; the majority were (78%) non-smokers. H. pylori was identified in 21.0% of the patients. Fluoroquinolone resistance was detected in 21.4% of the patients. Clarithromycin resistance was observed in 26.2%, with dual resistance identified in 4.8% of the patients. A high concordance was present with patients testing negative for H. pylori with both RUT and RT-PCR (94.3%). Only 57.6% of patients tested positive with both tests. However, 92.9% of RT-PCR positive patients had a positive genotype HelicoDR test. CONCLUSIONS: This data demonstrates a high rate of H. pylori resistance to both clarithromycin and fluoroquinolones. These should be avoided when treating H. pylori by utilizing different treatment regimes. Furthermore, we derived important data on the role of RT-PCR, which may be implemented in routine clinical practice.

Multiorganism sepsis secondary to enteric aorto-iliac graft fistulation.

A woman in her early 70s with a history of infrarenal aortic endarterectomy and aorto-bi-iliac Dacron grafting 4 years before presented with recurrent septicaemias, occasionally polymicrobial and caused by a wide variety of organisms. After treatment for her sixth bacteraemia, enteroscopy showed a small area of ulceration with synthetic graft material protruding into the distal duodenal lumen. This was followed by positron emission tomography/CT, which showed mild increase in tracer uptake in the same region localised by a previously placed haemoclip. Despite urgent vascular surgery to repair the duodenal fistulas and replace the grafts, the patient passed away. Our patient posed a diagnostic challenge due to repeated imaging studies of different modalities and routine endoscopy failing to show a source of sepsis. It is unique due to the variety of organisms cultured as a result of the enteric fistula.

Segmental colitis associated with diverticulosis: is it the coexistence of colonic diverticulosis and inflammatory bowel disease?

Segmental colitis associated with diverticulosis (SCAD) is an inflammatory process that affects colonic luminal mucosa in segments that are also affected by diverticulosis. Its prevalence varies between 1.15% and 11.4% amongst those suffering from diverticular disease (DD). Being closely associated with DD, it is slightly commoner in males and usually presents in the sixth decade of life. Although the exact pathogenesis of SCAD is unknown, it is probably heterogeneous and includes mechanisms that also play a part in inflammatory bowel disease (IBD). The clinical presentation is non-specific and similar to that of other pathologies involving the sigmoid colon, and its diagnosis is based on endoscopic findings in correlation with histology. Currently, there are no guidelines for its management, which is usually based on the administration of salicylates and antibiotics, with surgery being reserved for refractory cases. The rarity of SCAD may be multifactorial: whereas milder forms go undiagnosed or are attributed to DD, more severe forms can be misdiagnosed as IBD. This latter distinction is an important one to make, since SCAD and IBD differ as regards their natural history and prognosis, while very often no long-term medications are required in SCAD.

Aspiration of a speaking valve.

Foreign body aspiration (FBA) is a relatively common and serious condition that can result in a spectrum of presentations ranging from incidental to acutely life-threatening. Described here is a case of aspiration of a tracheo-oesophageal speaking valve through a permanent tracheostomy that went unnoticed for a number of years, and an overview of the technique used for its removal. A 70-year-old ex-heavy smoker with a permanent tracheo-oesophageal fistula presented with a relatively recent history of increasing shortness of breath, sputum purulence and haemoptysis. Further investigation with a CT scan and bronchoscopy revealed the presence of a foreign body within his right lower lobe bronchus which was later removed by advancing a flexible bronchoscope over a rigid one.