Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome.

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome predisposing affected individuals to gastrointestinal (GI) cancers through a high burden of polyposis. Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment. While most patients undergo colectomy at an early age, ongoing screening and surveillance of the upper gastrointestinal tract and rectal pouch must continue throughout adulthood. Endoscopic therapy of gastric, duodenal, ampullary and rectal pouch polyps is critical to reduce morbidity and cancer related mortality. Management of these lesions is not uniform, and is dependent on their location, size, histology, and risk of malignant potential. Medical therapies targeting pathways that reduce the malignant progression of pre-cancerous lesions have been studied for many years. While studies on the use of aspirin and non-steroidal anti-inflammatories (NSAIDs) in chemoprevention have shown encouraging results in Lynch syndrome and primary colorectal cancer, the potential benefits of these medications have not been duplicated in FAP cohorts. While data remains limited on chemoprevention in FAP, a number of randomized trials are currently underway examining targeted therapies with the potential to slow the progression of the disease. This review aims to provide an in-depth review of the literature on current endoscopic options and chemopreventive therapies targeting FAP. While the endoscopic management has robust data for its use, chemoprevention in FAP is still in its infancy. The complementary use of chemopreventive agents and endoscopic therapy for FAP patients is quickly becoming a growing and exciting area of research.

Does conventional early life academic excellence predict later life scientific discovery? An assessment of the lives of great medical innovators.

BACKGROUND: Perhaps, as never before, we need innovators. With our growing population numbers, and with increasing pressures on our education systems, are we in danger of becoming more rigid and formulaic and increasingly inhibiting innovation? When young can we predict who will become the great innovators? For example, in medicine, who will change clinical practice? AIMS: We therefore determined to assess whether the current academic excellence approach to medical school entrance would have captured previous great innovators in medicine, assuming that they should all have well fulfilled current entrance requirements. METHODS: The authors assembled a list of 100 great medical innovators which was then approved, rejected or added to by a jury of 12 MD fellows of the Royal Society of Canada. Two reviewers, who had taken both the past and present Medical College Admission Test as part of North American medical school entrance requirements, independently assessed each innovator's early life educational history in order to predict the innovator's likely success at medical school entry, assuming excellence in all entrance requirements. RESULTS: Thirty-one percent of the great medical innovators possessed no medical degree and 24% would likely be denied entry to medical school by today's standards (e.g. had a history of poor performance, failure, dropout or expulsion) with only 24% being guaranteed entry. Even if excellence in only one topic was required, the figure would only rise to 41% certain of medical school entry. CONCLUSION: These data show that today's medical school entry standards would have barred many great innovators and raise questions about whether we are losing medical innovators as a consequence. Our findings have important implications for promoting flexibility and innovation for medical education, and for promoting an environment for innovation in general.

Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease.

AIMS: After the diagnosis of immune-mediated inflammatory diseases (IMID) such as inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA), the incidence of psychiatric comorbidity is increased relative to the general population. We aimed to determine whether the incidence of psychiatric disorders is increased in the 5 years before the diagnosis of IMID as compared with the general population. METHODS: Using population-based administrative health data from the Canadian province of Manitoba, we identified all persons with incident IBD, MS and RA between 1989 and 2012, and cohorts from the general population matched 5 : 1 on year of birth, sex and region to each disease cohort. We identified members of these groups with at least 5 years of residency before and after the IMID diagnosis date. We applied validated algorithms for depression, anxiety disorders, bipolar disorder, schizophrenia, and any psychiatric disorder to determine the annual incidence of these conditions in the 5-year periods before and after the diagnosis year. RESULTS: We identified 12 141 incident cases of IMID (3766 IBD, 2190 MS, 6350 RA) and 65 424 matched individuals. As early as 5 years before diagnosis, the incidence of depression [incidence rate ratio (IRR) 1.54; 95% CI 1.30-1.84) and anxiety disorders (IRR 1.30; 95% CI 1.12-1.51) were elevated in the IMID cohort as compared with the matched cohort. Similar results were obtained for each of the IBD, MS and RA cohorts. The incidence of bipolar disorder was elevated beginning 3 years before IMID diagnosis (IRR 1.63; 95% CI 1.10-2.40). CONCLUSION: The incidence of psychiatric comorbidity is elevated in the IMID population as compared with a matched population as early as 5 years before diagnosis. Future studies should elucidate whether this reflects shared risk factors for psychiatric disorders and IMID, a shared final common inflammatory pathway or other aetiology.

Predictors of patient reluctance to wake early in the morning for bowel preparation for colonoscopy: a precolonoscopy survey in city-wide practice.

INTRODUCTION: Many endoscopists do not use split-dose bowel preparation (SDBP) for morning colonoscopies. Despite SDBP being recommended practice, they believe patients will not agree to take early morning bowel preparation (BP). We assessed patients' opinions about waking early for BP. METHODS: A self-administered survey was distributed between 08/2015 and 06/2016 to patients in Winnipeg, Canada when they attended an outpatient colonoscopy. Logistic regression was performed to determine predictors of reluctance to use early morning BP. RESULTS: Of the 1336 respondents (52 % female, median age 57 years), 33 % had used SDBP for their current colonoscopy. Of the 1336, 49 % were willing, 24 % neutral, and 27 % reluctant to do early morning BP. Predictors of reluctant versus willing were number of prior colonoscopies (OR 1.20; 95 %CI: 1.07 - 1.35), female gender (OR 1.65; 95 %CI: 1.19 - 2.29), unclear BP information (OR 1.86; 95 %CI: 1.21 - 2.85), high BP anxiety (OR 2.02; 95 %CI: 1.35 - 3.02), purpose of current colonoscopy being bowel symptoms (OR 1.40; 95 %CI: 1.00 - 1.97), use of 4 L of polyethylene glycol laxative (OR 1.45; 95 %CI: 1.02 - 2.06), not having SDBP (OR 1.96; 95 %CI: 1.31 - 2.93), and not having finished the laxative for the current colonoscopy (OR 1.66; 95 %CI: 1.01 - 2.73). Most of the same predictors were identified when reluctance was compared to willing or neutral, and in ordinal logistic regression. CONCLUSIONS: Almost three-quarters of patients do not express reluctance to get up early for BP. Among those who are reluctant, improving BP information, allaying BP-related anxiety, and use of low volume BP may increase acceptance of SDBP.

Independent Validation of a Self-Report Version of the IBD Disability Index (IBDDI) in a Population-Based Cohort of IBD Patients.

Introduction: A new clinician-administered inflammatory bowel disease (IBD) Disability Index (IBDDI) was recently developed and validated among a population in France. We aimed to validate the IBDDI in a North American setting and adapt for use as a self-report tool. Methods: Persons 18-65 years old from the population-based University of Manitoba IBD Research Registry were mailed a self-administered survey. This survey included the IBDDI and several scales that should correlate with a disability measure- the World Health Organization (WHO) Disability Assessment Scale (WHODAS) 2.0, Work and Social Adjustment Scale (WSAS), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the K6-Kessler Emotional Distress Scale. We used Pearson correlation coefficients to assess construct validity, Cronbach's alpha to assess internal consistency, and Factor analysis to assess which of the IBDDI items likely belonged to a single IBD-related disability factor. Results: In response to the survey request,1143 (46% of those contacted) participated (61% female, mean age 51, 52% with Crohn's disease). On an index scale from 0-100, 14% had a score ≥50 (extreme disability, 18% of those with Crohn's disease; 10% of those with ulcerative colitis). There were strong correlations between IBDDI and WSAS (0.76), WHODAS (0.76), K6 (0.73), and an inverse correlation with IBDQ (-0.86). The Cronbach's alpha was high (0.88). All but 2 items (number of liquid stools in the past week and arthritis/arthralgia) of the 14 identified for IBDDI loaded highly onto a single factor (factor loading > 0.40). Conclusions: The findings support the validity of this new self-report version of the IBDDI as a sound measure of disability in IBD.

Factors Associated with Anxiety About Colonoscopy: The Preparation, the Procedure, and the Anticipated Findings.

BACKGROUND: Previous research has assessed anxiety around colonoscopy procedures, but has not considered anxiety related to different aspects related to the colonoscopy process. AIMS: Before colonoscopy, we assessed anxiety about: bowel preparation, the procedure, and the anticipated results. We evaluated associations between patient characteristics and anxiety in each area. METHODS: An anonymous survey was distributed to patients immediately prior to their outpatient colonoscopy in six hospitals and two ambulatory care centers in Winnipeg, Canada. Anxiety was assessed using a visual analog scale. For each aspect, logistic regression models were used to explore associations between patient characteristics and high anxiety. RESULTS: A total of 1316 respondents completed the questions about anxiety (52% female, median age 56 years). Anxiety scores > 70 (high anxiety) were reported by 18% about bowel preparation, 29% about the procedure, and 28% about the procedure results. High anxiety about bowel preparation was associated with female sex, perceived unclear instructions, unfinished laxative, and no previous colonoscopies. High anxiety about the procedure was associated with female sex, no previous colonoscopies, and confusing instructions. High anxiety about the results was associated with symptoms as an indication for colonoscopy and instructions perceived as confusing. CONCLUSIONS: Fewer people had high anxiety about preparation than about the procedure and findings of the procedure. There are unique predictors of anxiety about each colonoscopy aspect. Understanding the nuanced differences in aspects of anxiety may help to design strategies to reduce anxiety, leading to improved acceptance of the procedure, compliance with preparation instructions, and less discomfort with the procedure.

Review article: changes in the epidemiology of inflammatory bowel disease-clues for aetiology.

BACKGROUND: The changing epidemiology of inflammatory bowel disease (IBD) in both the developed and developing worlds may provide insights into disease aetiology. Factors that impact on the gut microbiome are leading aetiological candidates. AIM: To review epidemiological studies and trends that identify risk factors for the development of IBD. METHODS: Studies that identified factors associated with the development of IBD differentially in children and adults were reviewed. There was a focus on epidemiological studies and on studies that involve the gut microbiome. RESULTS: Use of antibiotics has been shown to be associated with development of Crohn's disease in childhood (odds ratio, OR = 2.75, 95% CI 1.72-4.38). Breastfeeding has been protective against developing IBD (OR=0.69, 95% CI 0.51-0.94), but there is a paucity of data exploring duration of breastfeeding and timing of introduction of bottled milk or table food. Antibiotics and diet changes can also impact on adults enhancing the risk for IBD. Both smoking (OR=1.76, 95% CI 1.40-2.22) and oral contraceptives (relative risk=1.46, 95% CI 1.26-1.70) increase the risk for Crohn's disease and their use is associated with worse outcomes in Crohn's disease. It is unclear if their impact is mediated through the gut microbiome. CONCLUSIONS: A leading aetiological clue for IBD based on epidemiological studies is the antecedent use of antibiotics both for children and adults. Some dietary changes may be a risk for adults but there is a paucity of dietary data in children prior to IBD development. Both antibiotic use and dietary changes have the potential to impact the gut microbiome, which in turn can alter the gut immune response.

Markedly increased incidence of critical illness in adults with Type 1 diabetes.

AIMS: To compare the incidence of and mortality after intensive care unit admission in adults with paediatric-onset Type 1 diabetes vs the general population. METHODS: Using population-based administrative data from Manitoba, Canada, we identified 814 cases of paediatric-onset Type 1 diabetes, and 3579 general population controls matched on age, sex and region of residence. We estimated the incidence of intensive care unit admission in adulthood, and compared the findings between populations using incidence rate ratios and multivariable Cox proportional hazards regression, adjusting for age, sex, comorbidity and socio-economic status. We estimated age- and sex-standardized mortality rates after intensive care unit admission. RESULTS: Between January 2000 and October 2009, the average annual incidence of intensive care unit admission among prevalent cohorts was 910 per 100 000 in the Type 1 diabetes population, and 106 per 100 000 in matched controls, an eightfold increased risk (incidence rate ratio 8.6; 95% CI 5.5, 14.0). The adjusted risk of intensive care unit admission was elevated to a greater extent among women with Type 1 diabetes compared with matched women (hazard ratio 14.7; 95% CI 7.2, 29.4) than among men with Type 1 diabetes compared with matched men (hazard ratio 4.92; 95% CI 10.3, 2.36) The most common reasons for admission in the diabetes cohort were diabetic ketoacidosis, infection and ischaemic heart disease. At 30%, 5-year mortality was higher in the diabetes cohort than in the matched cohort (relative risk 5.7; 95% CI 1.2, 8.9). CONCLUSIONS: Compared with the general population, the risk of intensive care unit admission was higher in adults with paediatric-onset Type 1 diabetes, and mortality after admission was also higher.

A comparison of the gut microbiome between long-term users and non-users of proton pump inhibitors.

BACKGROUND: Proton pump inhibitor (PPI) use is associated with an increased risk of Clostridium difficile infection (CDI), though the mechanism is unclear. PPI induced alterations to the gut microbiome may facilitate the emergence of CDI, though the effects of PPIs on gut microbiota are not well characterised. [Correction added on 10 March 2016, after first online publication: microflora has been changed to microbiota throughout the article.] AIM: To compare the faecal microbiomes of long-term PPI users to those with no history of PPI use. METHODS: We used a population-based database to identify individuals with ≥5 years of continuous PPI use along with non-PPI using controls. Stool samples were subjected to microbiological analysis, with hierarchical clustering at genus level, along with alpha and beta diversity measures comparing the two groups. Metadata was accounted for using quantile regression to eliminate potential confounding variables in taxonomic abundance comparisons. RESULTS: Sixty-one subjects (32 PPI, 29 controls) were analysed. While no significant differences in alpha diversity were found between the PPI users and controls, a moderate shift of the PPI users away from the non-PPI user cluster in the beta diversity was observed. After controlling for pertinent confounders, we discovered a decrease in Bacteroidetes and an increase in Firmicutes at the phylum level. We also performed species classifications and found Holdemania filiformis and Pseudoflavonifractor capillosus to be increased and decreased in the PPI cohort, respectively. CONCLUSIONS: Long-term PPIs use has an effect on the gut microbiome. The alteration in the ratio of Firmicutes to Bacteroidetes may pre-dispose to the development of CDI.

Systematic review and meta-analysis of interventions for depression and anxiety in persons with multiple sclerosis.

BACKGROUND: Depression and anxiety are common in persons with multiple sclerosis (MS), and adversely affect fatigue, medication adherence, and quality of life. Though effective treatments for depression and anxiety exist in the general population, their applicability in the MS population has not been definitively established. OBJECTIVE: To determine the overall effect of psychological and pharmacological treatments for depression or anxiety in persons with MS. METHODS: We searched the Medline, EMBASE, PsycINFO, PsycARTICLES Full Text, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science, and Scopus databases using systematic review methodology from database inception until March 25, 2015. Two independent reviewers screened abstracts, extracted data, and assessed risk of bias and strength of evidence. We included controlled clinical trials reporting on the effect of pharmacological or psychological interventions for depression or anxiety in a sample of persons with MS. We calculated standardized mean differences (SMD) and pooled using random effects meta-analysis. RESULTS: Of 1753 abstracts screened, 21 articles reporting on 13 unique clinical trials met the inclusion criteria. Depression severity improved in nine psychological trials of depression treatment (N=307; SMD: -0.45 (95%CI: -0.74, -0.16)). The severity of depression also improved in three pharmacological trials of depression treatment (SMD: -0.63 (N=165; 95%CI: -1.07, -0.20)). For anxiety, only a single trial examined psychological therapy for injection phobia and reported no statistically significant improvement. CONCLUSION: Pharmacological and psychological treatments for depression were effective in reducing depressive symptoms in MS. The data are insufficient to determine the effectiveness of treatments for anxiety.

Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus

BACKGROUND & AIMS:: The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC. METHODS: A systematic literature search identified studies on the management of UC. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a working group of specialists. RESULTS: The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti-tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes. CONCLUSIONS: Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.(AU)

The impact of abdominal computed tomography in a tertiary referral centre emergency department on the management of patients with inflammatory bowel disease.

BACKGROUND: Although exposure to diagnostic radiation may be associated with increased risk of malignancy, the use of abdominal CT (ACT) in the last decade has increased for patients in the emergency department (ED). AIM: To examine the impact of ACT ordered in the ED on management of patients with inflammatory bowel diseases (IBD), as well as to quantify the cumulative effective dose (CED) of radiation received by these patients. METHODS: A total of 152 patients with Crohn's disease (CD) and 130 patients with ulcerative colitis (UC) that presented to the ED in a tertiary centre between 2009 and 2011 were identified. For patients that had an ACT, chart review assessed if the ACT findings changed clinical management. CED of diagnostic radiation (DR) was calculated for all imaging studies between 1 January 2006 and 30 August 2012. RESULTS: Abdominal CT use was 49% for CD and 19% for UC. ACTs with findings of penetrating/obstructive disease were 35% for CD. Urgent non-IBD-related diagnoses were found in 13% for CD and 28% for UC (P < 0.05). ACT caused a change in management in 81% of CD and 69% of UC patients. Mean CED from DR was 77.4 ± 63.0 mSv (median 53 mSv) for CD and 67.2 ± 51.0 mSv (median 56 mSv) for UC (P = 0.47). The CED for the 80-month period exceeded 75 mSv in 35% and 36% respectively (P = 0.99). CONCLUSIONS: Although abdominal CT often changes management of IBD patients in the emergency department, this population carries a very high-risk of radiation exposure. Efforts should be made to decrease this risk by development of low-radiation protocols, and wider use of MRI/ultrasound.

Predicting complicated Crohn's disease and surgery: phenotypes, genetics, serology and psychological characteristics of a population-based cohort.

BACKGROUND: Predictors of complicated Crohn's disease (CD), defined as stricturing or penetrating behaviour, and surgery have largely been derived from referral centre populations. AIM: To investigate whether serological markers, susceptibility genes or psychological characteristics are associated with complicated CD or surgery in a population-based cohort. METHODS: One hundred and eighty-two members of the Manitoba IBD Cohort with CD phenotyped using the Montreal classification underwent genetic and serological analysis at enrolment and after 5 years. One hundred and twenty-seven had paired sera at baseline and 5 years later and their data were used to predict outcomes at a median of 9.3 years. Serological analysis consisted of a seven antibody panel, and DNA was tested for CD-associated NOD2 variants (rs2066845,rs2076756,rs2066847), ATG16L1 (rs3828309, rs2241880) and IL23R (rs11465804). Psychological characteristics were assessed using semi-structured interviews and validated survey measures. RESULTS: Sixty-five per cent had complicated CD and 42% underwent surgery. Multivariate analysis indicated that only ASCA IgG-positive serology was predictive of stricturing/penetrating behaviour (OR = 3.01; 95% CI: 1.28-7.09; P = 0.01) and ileal CD (OR = 2.2; 95% CI: 1.07-4.54, P = 0.03). Complicated CD behaviour was strongly associated with surgery (OR = 5.6; 95% CI: 2.43-12.91; P < 0.0001), whereas in multivariate analysis, only ASCA IgG was associated (OR = 2.66; 95% CI, 1.40-5.06, P = 0.003). ASCA titre results were similar at baseline and follow-up. Psychological characteristics were not significantly associated with disease behaviour, serological profile or genotype. CONCLUSIONS: ASCA IgG at baseline was significantly associated with stricturing/penetrating disease at 9-10 years from diagnosis. Stricturing/penetrating disease was significantly associated with surgery. In a model including serology, the genotypes assessed did not significantly associate with complicated disease or surgery.

Gastrointestinal symptoms before and during menses in women with IBD.

BACKGROUND: It is believed that women with inflammatory bowel disease (IBD) have heightened symptoms around their menses. However, there is little information regarding normative changes and which symptoms emerge in relation to menses. AIM: To determine the relationship between gastrointestinal and other symptoms and menses in a population-based cohort of women with IBD vs. healthy women. METHODS: Women enrolled in the University of Manitoba IBD Research Registry who were between 18 and 65 years were mailed a survey. A control group of adult women were recruited through out-patient gynaecology clinics. Participants were asked to consider their menstrual periods in the recent several months and report on symptoms 1-5 days prior to and during the days of their menses. RESULTS: There were 151 premenopausal women with Crohn's disease (CD), 87 with ulcerative colitis (UC) and 156 premenopausal controls. Mean age of menses onset was similar in all three cohorts and the percentage in each group with regular menstrual periods was similar. Premenstrually, abdominal pain was less commonly reported in UC (36.8%) than CD (51%, P = 0.034) and controls (57.6%, P = 0.002). Premenstrually, and during menses diarrhoea was more commonly reported in CD (47.7% and 59.6% respectively) than UC (26.4% P = 0.001 and 42.5%, P = 0.01 respectively) and controls (24.4%, P < 0.0001 and 28.2%, P < 0.0001 respectively). Premenstrually, women with CD (46%) vs. UC (26%) were more likely to report worsening of their IBD symptoms (P = 0.0007), but there was no difference between CD (47%) and UC (39%) for reporting worsening during menses (P = 0.24). CONCLUSIONS: Compared to healthy women, women with IBD had similar symptom experiences premenstrually, except that those with CD were more likely to have increased diarrhoea premenstrually. During menses, women with CD or UC were more likely to experience diarrhoea than healthy controls.

Validating Crohn's disease activity indices for use in assessing postoperative recurrence.

BACKGROUND: The Crohn's Disease Activity Index (CDAI) has been used in medical trials with scores <150 indicative of remission. Its value in assessing postoperative recurrence is unknown. The objective of this study was to explore the utility of the CDAI in determining the presence or absence of symptomatic disease recurrence in patients having previously undergone ileocolic resection for Crohn's disease. METHODS: Ninety-three patients underwent clinical and colonoscopic evaluation within 12 months of ileocolic resection. Endoscopic appearance was assessed using the Rutgeerts score (i0-i4). Symptomatic disease recurrence was defined by the composite of symptom severity warranting therapy and an endoscopic score ≥ i2. CDAI scores were calculated. Comparisons were made using the receiver operator curve (ROC). RESULTS: Thirty-nine (42%) patients had recurrent disease (22% symptomatic, 20% endoscopic only) at 12 months. Median CDAI for symptomatic recurrence was 198 (interquartile range [IQR]: 106-293), 80 for asymptomatic subjects (IQR 35-115). The area under the ROC curve for symptomatic disease and CDAI was 0.78 (95% confidence interval [CI] 0.64-0.91). Recurrence was best predicted by a CDAI of ≥ 148 (sensitivity 70%, specificity 81%). A strong linear relationship existed between the CDAI and Inflammatory Bowel Disease Questionnaire (r = 0.82). CONCLUSIONS: The CDAI performs reasonably well in the postoperative setting and 150 appears the best cutpoint for indicating symptomatic disease. However, it is likely not suitable for use as the primary outcome measure. These data suggest that a combination of symptom assessment plus endoscopic evidence of recurrence should remain the gold standard definition for assessing outcomes in postoperative CD trials.

Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population.

Most of the genetic risk for rheumatoid arthritis (RA) is conferred by 'shared epitope' (SE), encoding alleles of HLA-DRB1. Specific North American Native (NAN) populations have RA prevalence rates of 2-5%, representing some of the highest rates estimated worldwide. As many NAN populations also demonstrate a high background frequency of SE, we sought to determine whether other genetic factors contribute to disease risk in this predisposed population. RA patients (n=333) and controls (n=490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL. Our findings indicate that SE is prevalent and represents a major genetic risk factor for RA in this population (82% cases versus 68% controls, odds ratio=2.2, 95% confidence interval 1.6-3.1, P<0.001). We also demonstrate that in the presence of SE, the minor allele of MMEL1-TNFRSF14 significantly reduces RA risk in a dominant manner, whereas TRAF1-C5 increases the risk. These findings point to the importance of non-HLA genes in determining RA risk in a population with a high frequency of disease predisposing HLA-DRB1 alleles.

Detecting colorectal cancer by 1H magnetic resonance spectroscopy of fecal extracts.

Colorectal cancer is one of the most common cancers in the western world. Its early detection has been found to improve the prognosis of the patient, providing a wide window of opportunity for successful therapeutic interventions. However, current diagnostic techniques all have some limitations; there is a need to develop a better technique for routine screening purposes. We present a new methodology based on magnetic resonance spectroscopy of fecal extracts for the non-invasive detection of colorectal cancer. Five hundred twenty-three human subjects (412 with no colonic neoplasia and 111 with colorectal cancer, who were scheduled for colonoscopy or surgery) were recruited to donate a single sample of stool. One-dimensional (1)H magnetic resonance spectroscopy (MRS) experiments were performed on the supernatant of aqueous dispersions of the stool samples. Using a statistical classification strategy, several multivariate classifiers were developed. Applying the preprocessing, feature selection and classifier development stages of the Statistical Classification Strategy led to approximately 87% average balanced sensitivity and specificity for both training and monitoring sets, improving to approximately 92% when only crisp results, i.e. class assignment probabilities > or =75%, are considered. These results indicate that (1)H magnetic resonance spectroscopy of human fecal extracts, combined with appropriate data analysis methodology, has the potential to detect colorectal neoplasia accurately and reliably, and could be a useful addition to the current screening tools.