The impact of donor biological variation on the quality and function of cold-stored platelets.

BACKGROUND AND OBJECTIVES: Room temperature-stored platelets (RTPs) maximize platelet viability but limit shelf life. The aims of this study were to investigate the impact of donor variability on cold-stored platelets (CSPs) and RTP, to determine whether RTP quality markers are appropriate for CSP. MATERIALS AND METHODS: Double platelet donations (n = 10) were collected from consented regular male donors stored in 100% plasma. A full blood count, donor age, weight, height and body mass index (BMI) were collected at the time of donation. Platelet donations were split equally into two bags, and assigned to non-agitated CSP or agitated RTP. The quality and function of platelets were assessed throughout the standard 7 days of storage and at expiry (day 8). Non-parametric statistical analyses were used to analyse results given the small sample size. RESULTS: As expected, there were significant differences between CSP and RTP throughout storage including a reduction in CSP concentration as well as a loss of swirling. Furthermore, a significant increase in CSP exhibiting activation and apoptotic markers was observed. Platelet concentrations were further impacted by donor BMI, and donors with the highest BMI (>29) had the lowest platelet concentration and activation response at the end of CSP storage. CONCLUSION: Platelet quality and functionality play a vital role in transfusion outcomes; however, blood components are inherently variable. This study demonstrated, for the first time, the specific impact of donor BMI on CSP quality and function and highlights the requirement for novel quality markers for assessing CSPs.

High diagnostic yield despite a lower completion rates for inpatient versus outpatient colon and pan-intestinal capsule endoscopy: a nested case-control study.

BACKGROUND: Increased familiarity with capsule endoscopy (CE) has been associated with a growing demand for urgent inpatient procedures. Limited data exists comparing the effect of admission status on colon capsule (CCE) and pan-intestinal capsule (PIC) performance. We aimed to compare the quality of inpatient versus outpatient CCE and PIC studies. METHODS: A retrospective nested case-control study. Patients were identified from a CE database. PillCam Colon 2 Capsules with standard bowel preparation and booster regimen were used in all studies. Basic demographics and key outcome measures were documented from procedure reports and hospital patient records, and compared between groups. RESULTS: 105 subjects were included, 35 cases and 70 controls. Cases were older, were more frequently referred with active bleeding and had more PICs. The diagnostic yield was high at 77% and was similar in both groups. Completion rates were significantly better for outpatients, 43% (n = 15) v's 71% (n = 50), OR 3, NN3. Neither gender nor age affected completion rates. Completion rates and preparation quality were similar for CCE and PIC inpatient procedures. CONCLUSION: Inpatient CCE and PIC have a clinical role. There is an increased risk of incomplete transit in inpatients, and strategies to mitigate against this are needed.

Accuracy of Transient Elastography in Assessing Fibrosis at Diagnosis in Naïve Patients With Primary Biliary Cholangitis: A Dual Cut-Off Approach.

BACKGROUND AND AIMS: Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Noninvasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis (AF) at disease presentation in PBC. APPROACH AND RESULTS: We collected data from 167 consecutive treatment-naïve PBC patients who underwent liver biopsy (LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to the Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves (AUROCs) for AF (Ludwig stage ≥III). Effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. The derivation cohort consisted of 126 patients with valid LSM and LB; VCTE identified patients with AF with an AUROC of 0.89. LSM cutoffs ≤6.5 and >11.0 kPa enabled to exclude and confirm, respectively, AF (negative predictive value [NPV] = 0.94; positive predictive value [PPV] = 0.89; error rate = 5.6%). These values were externally validated in an independent cohort of 91 PBC patients (NPV = 0.93; PPV = 0.89; error rate = 8.6%). Multivariable analysis found that the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry. CONCLUSIONS: In a multicenter study of treatment-naïve PBC patients, we identified two cutoffs (LSM ≤6.5 and >11.0 kPa) able to discriminate at diagnosis the absence or presence, respectively, of AF in PBC patients, with external validation. In patients with LSM between these two cutoffs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.

Measurement of Gamma Glutamyl Transferase to Determine Risk of Liver Transplantation or Death in Patients With Primary Biliary Cholangitis.

BACKGROUND & AIMS: Gamma-glutamyltransferase (GGT) is a serum marker of cholestasis. We investigated whether serum level of GGT is a prognostic marker for patients with primary biliary cholangitis (PBC). METHODS: We analyzed data from patients with PBC from the Global PBC Study Group, comprising 14 centers in Europe and North America. We obtained measurements of serum GGT at baseline and time points after treatment. We used Cox model hazard ratios to evaluate the association between GGT and clinical outcomes, including liver transplantation and liver-related death. RESULTS: Of the 2129 patients included in our analysis, 281 (13%) had a liver-related clinical endpoint. Mean age at diagnosis was 53 years and 91% of patients were female patients. We found a correlation between serum levels of GGT and alkaline phosphatase (ALP) (r = 0.71). Based on data collected at baseline and yearly for up to 5 years, higher serum levels of GGT were associated with lower hazard for transplant-free survival. Serum level of GGT at 12 months after treatment higher than 3.2-fold the upper limit of normal (ULN) identified patients who required liver transplantation or with liver-related death at 10 years with an area under the receiver operating characteristic curve of 0.70. The risk of liver transplantation or liver-related death in patients with serum level of GGT above 3.2-fold the ULN, despite level of ALP lower than 1.5-fold the ULN, was higher compared to patients with level of GGT lower than 3.2-fold the ULN and level of ALP lower than 1.5-fold the ULN (P < .05). Including information on level of GGT increased the prognostic value of the Globe score. CONCLUSIONS: Serum level of GGT can be used to identify patients with PBC at risk for liver transplantation or death, and increase the prognostic value of ALP measurement. Our findings support the use of GGT as primary clinical endpoint in clinical trials. In patients with low serum level of ALP, a high level of GGT identifies those who might require treatment of metabolic disorders or PBC treatment escalation.

Multiple therapeutic targets in rare cholestatic liver diseases: Time to redefine treatment strategies.

Primary biliary cholangitis and primary sclerosing cholangitis are rare diseases affecting the bile ducts and the liver. The limited knowledge of their pathogenesis leads to limited therapeutic options. Nevertheless, the landscape of novel therapies for these cholangiopathies is now rapidly changing, providing new treatment opportunities for patients and clinicians involved in their care. The aim of this review is to summarize the evidence of novel molecules under investigation for primary biliary cholangitis and primary sclerosing cholangitis and to discuss how they can potentially change current treatment paradigms.

Helicobacter pylori: High dose amoxicillin does not improve primary or secondary eradication rates in an Irish cohort.

BACKGROUND: Helicobacter pylori (H. pylori) eradication rates have fallen globally, likely in large part due to increasing antibiotic resistance to traditional therapy. In areas of high clarithromycin and metronidazole resistance such as ours, Maastricht VI guidelines suggest high dose amoxicillin dual therapy (HDADT) can be considered, subject to evidence for local efficacy. In this study we assess efficacy of HDADT therapy for H. pylori eradication in an Irish cohort. AIM: To assess the efficacy of HDADT therapy for H. pylori eradication in an Irish cohort as both first line, and subsequent therapy for patients diagnosed with H. pylori. METHODS: All patients testing positive for H. pylori in a tertiary centre were treated prospectively with HDADT (amoxicillin 1 g tid and esomeprazole 40 mg bid × 14 d) over a period of 8 months. Eradication was confirmed with Urea Breath Test at least 4 wk after cessation of therapy. A delta-over-baseline > 4% was considered positive. Patient demographics and treatment outcomes were recorded, analysed and controlled for basic demographics and prior H. pylori treatment. RESULTS: One hundred and ninety-eight patients were identified with H. pylori infection, 10 patients were excluded due to penicillin allergy and 38 patients refused follow up testing. In all 139 were included in the analysis, 55% (n = 76) were female, mean age was 46.6 years. Overall, 93 (67%) of patients were treatment-naïve and 46 (33%) had received at least one previous course of treatment. The groups were statistically similar. Self-reported compliance with HDADT was 97%, mild side-effects occurred in 7%. There were no serious adverse drug reactions. Overall the eradication rate for our cohort was 56% (78/139). Eradication rates were worse for those with previous treatment [43% (20/46) vs 62% (58/93), P = 0.0458, odds ratio = 2.15]. Age and Gender had no effect on eradication status. CONCLUSION: Overall eradication rates with HDADT were disappointing. Despite being a simple and possibly better tolerated regime, these results do not support its routine use in a high dual resistance country. Further investigation of other regimens to achieve the > 90% eradication target is needed.

Addition of castor oil as a booster in colon capsule regimens significantly improves completion rates and polyp detection.

BACKGROUND: Incomplete excretion rates are problematic for colon capsule endoscopy (CCE). Widely available booster regimens are suboptimal. Recently published data on one day preparation CCE protocol using castor oil appeared effective. AIM: To assess the impact of adding castor oil to a standard split-dose (2-d) preparation in an unselected Western patient cohort. METHODS: All patients aged 18 or more referred to our unit for a CCE over a 5-mo period were prospectively recruited. Controls were retrospectively identified from our CCE database. All patients received split bowel preparation with Moviprep® [polyethylene glycol (PEG)-3350, sodium sulphate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution; Norgine B. V, United States], a PEG-based solution used predominantly in our colonoscopy practice. Control booster regimen included Moviprep® with 750 mL of water (booster 1) on reaching the small bowel. A further dose of Moviprep® with 250 mL of water was given 3 h later and a bisacodyl suppository (Dulcolax®) 10 mg after 8 h, if the capsule was not excreted. In addition to our standard booster regimen, cases received an additional 15 mL of castor oil given at the time of booster 1. A nested case control design with 2:1 ratio (control:case) was employed. Basic demographics, completion rates, image quality, colonic transit time, diagnostic yield and polyp detection were compared between groups, using a student t or chi-square tests as appropriate. RESULTS: One hundred and eighty-six CCEs [mean age 60 years (18-97), 56% females, n = 104], including 62 cases have been analysed. Indication breakdown included 96 polyp surveillance (51.6%), 42 lower gastrointestinal symptoms (22.6%), 28 due to incomplete colonoscopy (15%), 18 anaemia (9.7%) and 2 inflammatory bowel disease surveillance (1.1%). Overall, CCE completion was 77% (144/186), image quality was adequate/diagnostic in 91% (170/186), mean colonic transit time was 3.5 h (0.25-13), and the polyp detection rate was 57% (106/186). Completion rates were significantly higher with castor oil, 87% cases (54/62) vs 73% controls (90/124), P = 0.01. The number needed to treat with castor oil to result in an additional complete CCE study was 7, absolute risk reduction = 14.52%, 95% confidence interval (CI): 3.06- 25.97. This effect of castor oil on excretion rates was more significant in the over 60 s, P < 0.03, and in females, P < 0.025. Similarly, polyp detection rates were higher in cases 82% (51/62) vs controls 44% (55/124), P = 0.0001, odds ratio 5.8, 95%CI: 2.77-12.21. Colonic transit times were similar, 3.2 h and 3.8 h, respectively. Image quality was similar, reported as adequate/diagnostic in 90% (56/62) vs 92% (114/124). CONCLUSION: In our capsule endoscopy centre, castor oil addition as a CCE booster significantly improved completion rates and polyp detection in an unselected Western cohort.

Colon capsule endoscopy is a viable alternative to colonoscopy for the investigation of intermediate- and low-risk patients with gastrointestinal symptoms: results of a pilot study.

Background and study aims Colon capsule endoscopy (CCE) is a recommended viable alternative to colonoscopy for colonic visualisation in a variety of clinical settings with proven efficacy in polyp detection, surveillance, screening and Inflammatory Bowel Disease (IBD) assessment. CCE efficacy in an unselected average risk symptomatic cohort has yet to be established. The aim of this study was to determine the feasibility of CCE imaging assessment in average risk symptomatic patients as an alternative to colonoscopy with and without additional biomarker assessment. Patients and methods This was a prospective, single-center comparison study of colonoscopy, CCE and biomarker assessment. Results Of 77 invited subjects, 66 underwent both a CCE and colonoscopy. A fecal immunochemical test (FIT) and fecal calprotectin (FC) were available in 56 and 59 subjects. In all 64 % (n = 42) had any positive finding with 16 (24 %) found to have significant disease (high-risk adenomas, IBD) on colonoscopy. The CCE completion rate was 76 %, five (8 %) had an inadequate preparation, the CCE polyp detection rate was high at 35 %. The sensitivity, specificity, positive and negative predictive values of CCE for significant disease were 81 %, 98 %, 93 % and 94 % respectively. In addition, three (5 %) significant small bowel diagnoses were made on CCE. FC and FIT were frequently elevated in patients with both colitis (5/7, 71 %) and high-risk adenomas (4/7 57 %). While both had a low positive predictive value for clinically significant disease, FIT 32 % and FC 26 %. Conclusions CCE is a safe and effective alternative to colonoscopy in symptomatic average risk patients with or without the addition of biomarker screening.

Quality of life in patients with primary biliary cholangitis: A cross-geographical comparison.

BACKGROUND & AIMS: Several symptoms impair the quality of life (QoL) of patients with primary biliary cholangitis (PBC). They are reported to vary significantly in different countries. Aim of our study was to explore whether there is a geographical clustering that accounts for symptoms in PBC. METHODS: Data was analysed from four cohorts of PBC patients from the UK, Spain, Japan and Italy using the PBC-27 scale. RESULTS: Overall, 569 patients from four cohorts were identified, including 515 females (90.5%) with a mean age of 61 years. The analysis provided evidence for strict factorial invariance of the scale, a robust indicator of its validity for cross-cultural research. The mean of the fatigue domain of British patients was significantly greater than that of the Japanese (p â€‹< â€‹0.05), Italian (p â€‹< â€‹0.05), and Spanish patients (p â€‹< â€‹0.001). The mean of the cognitive domain after 54 years of age, was significantly greater in the British patients than in the Japanese (p â€‹< â€‹0.05) and Spanish patients (p â€‹< â€‹0.01). However, after 69 years of age, there were not significant differences between countries. The mean of the emotion domain after 54 years of age, was greater in the British that in the Spanish (p â€‹< â€‹0.01) and Italian patients (p â€‹< â€‹0.01). CONCLUSIONS: Differences in the four countries concerning fatigue, cognitive and emotional dysfunction were found. The association of latitude and symptoms might provide new insights into the role of sun exposure, genetics and/or cultural component into disease phenotype in PBC.

New Therapeutic Targets in Autoimmune Cholangiopathies.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune cholangiopathies characterized by limited treatment options. A more accurate understanding of the several pathways involved in these diseases has fostered the development of novel and promising targeted drugs. For PBC, the characterization of the role of farnesoid X receptor (FXR) and perixosome-proliferator activated receptor (PPAR) has paved the way to several clinical trials including different molecules with choleretic and antinflammatory action. Conversely, different pathogenetic models have been proposed in PSC such as the "leaky gut" hypothesis, a dysbiotic microbiota or a defect in mechanisms protecting against bile acid toxicity. Along these theories, new treatment approaches have been developed, ranging from drugs interfering with trafficking of lymphocytes from the gut to the liver, fecal microbiota transplantation or new biliary acids with possible immunomodulatory potential. Finally, for both diseases, antifibrotic agents are under investigation. In this review, we will illustrate current understanding of molecular mechanisms in PBC and PSC, focusing on actionable biological pathways for which novel treatments are being developed.

The Unsolved Link of Genetic Markers and Crohn's Disease Progression: A North American Cohort Experience.

BACKGROUND: While progress has been made in the identification of Crohn's disease (CD) susceptibility loci, efforts to identify a genetic basis for disease progression have been less fruitful. The specific aim of this study was to build upon the major genetic advances made in IBD by applying genome-wide technologies toward predicting disease progression in CD. METHODS: Crohn's disease cases (n = 1495) from 3 IBD centers were reviewed by experienced physicians. Clinical and demographic details were collected, focusing on the time to first disease progression. Genome-wide association (GWA) analysis was carried out on 3 clinical outcomes: 1) time to disease progression; 2) time to first abdominal surgery; and 3) a binary analysis of indolent vs progressive disease. Cox-proportional hazard and logistic regression models were used. RESULTS: A GWA analysis was carried out to determine any genetic variation associated with the time to disease progression; 662 cases were included after quality control (QC) and exclusion of any cases with B2/B3 behavior at baseline (n = 450). There were 1360 cases included after QC in the time to abdominal surgery analysis. No variant reached genome-wide significance in any of the 3 analyses performed. Eight known IBD susceptibility single nucleotide polymorphism (SNPs) were found to be associated with time-to-abdominal surgery SMAD3 (rs17293632), CCR6 (rs1819333), CNTF (rs11229555), TSPAN14 (rs7097656), CARD9 (rs10781499), IPMK (rs2790216), IL10 (rs3024505), and SMURF1 (rs9297145) (P < 0.05). CONCLUSION: Our GWA study failed to show any SNP-phenotype association reaching genome-wide significance. It is likely that multiple variables affect disease progression, with genetic factors potentially having only a small effect size.

Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease.

Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature. To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Follow-up immunohistochemistry analysis verified the presence of EPHX2 protein in infiltrated immune cells from Crohn's patient tissue biopsies. We further demonstrated that GSK2256294, a clinical EPHX2i, reduced the production of IL2, IL12p70, IL10 and TNFα in both ulcerative colitis and Crohn's disease patient-derived explant cultures. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1ß in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD.

Biomarkers as potential treatment targets in inflammatory bowel disease: A systematic review.

There is increasing interest in the concept of 'treat-to-target' in inflammatory bowel disease as a mechanism to standardize management and prevent complications. While clinical, radiographic and endoscopic treatment end points will figure prominently in this promising management paradigm, the role that noninvasive biomarkers will play is currently undefined. The goal of the present systematic review was to investigate the potential value of biomarkers as treatment targets in inflammatory bowel disease, with particular focus on those best studied: serum C-reactive protein (CRP) and fecal calprotectin. In Crohn disease, elevated CRP levels at baseline predict response to anti-tumour necrosis factor agents, and normalization is usually associated with clinical and endoscopic remission. CRP and hemoglobin levels can be used to help predict clinical relapse in the context of withdrawal of therapy. Ultimately, the authors conclude that currently available biomarkers should not be used as treatment targets in inflammatory bowel disease because they have inadequate operational characteristics to make them safe surrogates for clinical, endoscopic and radiographic evaluation. However, CRP and fecal calprotectin are important adjunctive measures that help alert the clinician to pursue further investigation.

Higher Rates of Dose Optimisation for Infliximab Responders in Ulcerative Colitis than in Crohn's disease.

BACKGROUND: Studies have demonstrated the benefit of dose optimisation in the setting of secondary loss of response to infliximab in inflammatory bowel disease. AIM: The aim of our study was to retrospectively investigate the rates of dose optimisation in an inflammatory bowel disease cohort receiving maintenance infliximab therapy to determine if there are different rates of dose optimisation between CD and UC cases and what impact this has on the durability of treatment effect. METHODS: Cases receiving infliximab for treatment of IBD between January 2008 and February 2014 were identified from an infusion centre database. Cases receiving ≥ 4 infusions were included in the study. Details of infusion dosing and timing were obtained. A dose increase from 5mg/kg to 10mg/kg or a reduction in the dosing interval was considered a dose optimisation. RESULTS: A total of 412 cases were included in the study; 52.7% required at least one dose optimisation. Dose optimisation was more common in UC than in CD cases [67.2% vs 46.3%, p = 0.00006]. The median time to dose optimisation was 7 months (95% confidence interval [CI] 4.8-9.2) for UC cases and 27 months [95% CI 7.3-46.7] for CD cases, p = 0.00003. CONCLUSIONS: Here we have shown that dose optimisation is required more frequently in UC than in CD, with a significantly shorter time to dose optimisation for UC cases than CD cases. The majority of cases responding to induction therapy with infliximab will have a sustained response to therapy, but over 50% will require a dose optimisation during their treatment.

The clinical significance of antimicrobial serologic responses within an Irish Crohn's disease population.

INTRODUCTION: A hyper-responsive adaptive immunologic response to a variety of microbial antigens has been described in Crohn's disease (CD) patients and elevated levels of a number of antibodies have been identified in the sera of CD patients. To date, the serological profiles of an Irish CD population have not been characterized. OBJECTIVES: The aim of this study is to determine the serological profile of Irish patients with CD. Second, we aim to assess the correlation, if any, between serological profile and disease phenotype within this cohort. METHODS: A total of 179 consecutive adults with CD attending a specialist inflammatory bowel disease clinic at a university hospital were recruited. Blood samples were taken and sera were analysed for the expression of pANCA and Crohn's related antibodies. RESULTS: pANCA was present in 47/179 (26.3%), anti-OmpC antibodies were present in 49/179 (27.4%), anti-Saccharomyces cervisiae (ASCA) in 64/179 (35.75%), ASCA IgA in 56/179 (31.28%) and ASCA IgG in 37/179 (20.67%), and anti-CBir antibodies in 97/179 (54.18%). The presence of ASCA IgA (P=0.031), ASCA IgG (P=0.007) and anti-CBir antibodies (P=0.003) were all significantly associated with small bowel involvement. Anti-OmpC, ASCA IgA and anti-CBir antibodies' positivity were all associated with complicated disease behaviour, whereas ANCA positivity was associated with inflammatory disease. CONCLUSION: Our study supports previous findings of an association between serological profiles and disease behaviour and a corresponding association with increased need for surgery. In this genetically homogenous Irish CD study group, the levels of specific antibody responses to commensal gut flora are lower than reported previously in other European and American populations.

Toward graduate medical education (GME) accountability: measuring the outcomes of GME institutions.

PURPOSE: Graduate medical education (GME) plays a key role in the U.S. health care workforce, defining its overall size and specialty distribution and influencing physician practice locations. Medicare provides nearly $10 billion annually to support GME and faces growing policy maker interest in creating accountability measures. The purpose of this study was to develop and test candidate GME outcome measures related to physician workforce. METHOD: The authors performed a secondary analysis of data from the American Medical Association Physician Masterfile, National Provider Identifier file, Medicare claims, and National Health Service Corps, measuring the number and percentage of graduates from 2006 to 2008 practicing in high-need specialties and underserved areas aggregated by their U.S. GME program. RESULTS: Average overall primary care production rate was 25.2% for the study period, although this is an overestimate because hospitalists could not be excluded. Of 759 sponsoring institutions, 158 produced no primary care graduates, and 184 produced more than 80%. An average of 37.9% of internal medicine residents were retained in primary care, including hospitalists. Mean general surgery retention was 38.4%. Overall, 4.8% of graduates practiced in rural areas; 198 institutions produced no rural physicians, and 283 institutions produced no Federally Qualified Health Center or Rural Health Clinic physicians. CONCLUSIONS: GME outcomes are measurable for most institutions and training sites. Specialty and geographic locations vary significantly. These findings can inform educators and policy makers during a period of increased calls to align the GME system with national health needs.

Isolated active ileitis: is it a mild subtype of Crohn's disease?

BACKGROUND: Ileal intubation is being increasingly performed at colonoscopy and has in turn lead to an increasingly recognized subgroup of patients-those with mild terminal ileal inflammation, an entity that we have coined isolated active ileitis (IAI). The aims of this study were to define the natural history of IAI and determine if IAI shares a similar genetic and serologic profile with Crohn's disease (CD). METHODS: Patients with IAI were identified from our institution's histopathology and endoscopy databases. Cases attended for repeat colonoscopy and blood were analyzed for the expression of antineutrophil cytoplasmic antibody, anti-OmpC, anti-Saccharomyces cerevisiae antigen (ASCA) IgA, ASCA IgG, and anti-CBir antibodies and NOD2 genotyping. Age and sex-matched healthy controls, CD, and UC cases were also recruited. RESULTS: Sixty-three patients with IAI were recruited. There was no significant difference in the prevalence of antibodies between IAI cases and healthy controls for antineutrophil cytoplasmic antibody, OmpC, ASCA IgA, or ASCA IgG. The presence of all 5 antibodies was significantly higher in the CD group than the IAI group, P < 0.05. There were 28.6% of CD cases that carried one or more NOD2 variants, compared to 26.2% of the IAI cohort and 6.1% of healthy controls. Forty-three cases underwent follow-up ileocolonoscopy. Six of 43 cases (14%) had definite CD. CONCLUSIONS: A majority of IAI cases developed persistent symptoms and terminal ileal abnormalities; however, only 14% developed classical, histological, or radiological features of CD. Although patients with IAI have a low level of seropositivity, similar to healthy controls, they do share an excess of NOD2 mutations with CD cases.

Drug treatment of eosinophilic oesophagitis.

Eosinophilic oesophagitis is a clinicopathological disease characterized by oesophageal eosinophilia and gastrointestinal symptoms. Currently, the optimal treatment regimens remain unclear. The pathogenesis of eosinophilic oesophagitis appears to involve immune dysregulation, while acid reflux may have a secondary role; the mainstays in treatment are aimed principally at these dual processes. While a trial of a PPI is worthwhile it is likely that PPI therapy is treating concurrent acid reflux rather than true eosinophilic oesophagitis. Dietary elimination with elemental feed is safe but poorly tolerated. Swallowed topical steroids are the mainstay of commercially available therapies. Both fluticasone and budesonide have been proven to be beneficial both symptomatically and in reducing oesophageal eosinophil counts in the short and medium term. Basic studies have determined a role for IL-5 in oesophageal remodelling in eosinophilic esophagitis. Initial clinical studies have shown single or multiple infusions of monoclonal antibody to IL-5 to be well tolerated and to cause a long-term decrease in both peripheral and sputum eosinophil count in these eosinophil driven conditions. At present, swallowed corticosteroids are the mainstay of treatment for patients with eosinophilic oesophagitis in patients failing PPI therapy. Studies have been heterogenous in their diagnostic criteria for eosinophilic oesophagitis and in the definition of response to therapy, making comparison of results difficult.

Eosinophilic oesophagitis: an Irish experience.

INTRODUCTION: Eosinophilic oesophagitis is a recently recognized oesophageal disorder characterized by a combination of clinical and endoscopic features as well as the histological finding on oesophageal biopsy of greater than 15 eosinophils per high powered field. Recent reports suggest eosinophilic oesophagitis is increasing in incidence and this increase cannot be fully explained by increased recognition of the disorder. The aim of this retrospective study was to assess the incidence of eosinophilic oesophagitis within the catchment area of a tertiary referral hospital in southwest Dublin, Ireland. METHODS: The histopathology database at the Adelaide and Meath Hospital was used to identify all oesophageal biopsies obtained between January 2000 and July 2008 reported to show evidence of oesophagitis. Biopsy samples with greater than 15 eosinophils per high powered field in at least two fields were highlighted as possible eosinophilic oesophagitis. The oesophageal biopsies of patients identified in this way were reviewed by a histopathologist with a special expertise in gastroenterology for features suggestive of eosinophilic oesophagitis. RESULTS: Twenty-five thousand three hundred and sixty-five upper gastrointestinal endoscopies were performed between January 2000 and July 2008. A total of 11 072 sets of oesophageal biopsies were taken and 1364 (12.3%) of these revealed evidence of oesophagitis. Only 13 (0.1%) patients had oesophageal biopsies showing greater than 15 eosinophils per high powered field. The median age of this patient group was 23 years (interquartile range 10.5-50.5 years), with 46% of patients under 18 years at the time of diagnosis. The male to female ratio was 5.5 : 1 compared with 1.1 : 1 in the oesophagitis group as a whole, (P=0.002). There was no significant association between endoscopic findings or presenting complaints and the average number of eosinophils per high powered field. The average number of biopsies taken in patients with endoscopic findings suggestive of eosinophilic oesophagitis was 3.75 compared with 1 in patients without those features, (P=0.01). CONCLUSION: Our findings suggest that eosinophilic oesophagitis is a rare disorder predominantly affecting young men.