Inflammatory bowel disease patient perceptions of diagnostic and monitoring tests and procedures.

BACKGROUND: Inflammatory Bowel Disease (IBD) with its high incidence and prevalence rates in Canada generates a heavy burden of tests and procedures. The purpose of this study is to gain a better understanding of the transfer of information from physician to patient, as well as the patient understanding and perceptions about the tests and procedures that are ordered to them in the context of IBD diagnosis and monitoring. METHODS: An online questionnaire was completed by 210 IBD patients in Canada. Information on the five most-often used tests or procedures in IBD diagnosis/monitoring was collected. These include: general blood test, colonoscopy, colon biopsy, medical imaging and stool testing. RESULTS: The general blood test is both the most ordered and most refused tool. It is also the one with which patients are the least comfortable, the one that generates the least concern and the one about which physicians provide the least information. The stool test is the test/procedure with which patients are the most comfortable. Procedures raise more concerns among patients and physicians provide more information about why they are needed, their impact and the risks they present. Very little information is provided to patients about the risks of having false positives or negative tests. CONCLUSIONS: This study provides an initial understanding of patient perceptions, the transfer of information from a physician to a patient and a patient's understanding of the tests and procedures that will be required to treat IBD throughout what is a lifelong disease. The present study takes a first step in better understanding the acceptance of the test or procedure by IBD patients, which is essential for them to adhere to the monitoring process.

Improving Reliability of Immunological Assays by Defining Minimal Criteria for Cell Fitness.

Human PBMC-based assays are often used as biomarkers for the diagnosis and prognosis of disease, as well as for the prediction and tracking of response to biological therapeutics. However, the development and use of PBMC-based biomarker assays is often limited by poor reproducibility. Complex immunological assays can be further complicated by variation in cell handling before analysis, especially when using cryopreserved cells. Variation in postthaw viability is further increased if PBMC isolation and cryopreservation are done more than a few hours after collection. There is currently a lack of evidence-based standards for the minimal PBMC viability or "fitness" required to ensure the integrity and reproducibility of immune cell-based assays. In this study, we use an "induced fail" approach to examine the effect of thawed human PBMC fitness on four flow cytometry-based assays. We found that cell permeability-based viability stains at the time of thawing did not accurately quantify cell fitness, whereas a combined measurement of metabolic activity and early apoptosis markers did. Investigation of the impact of different types and levels of damage on PBMC-based assays revealed that only when cells were >60-70% live and apoptosis negative did biomarker values cease to be determined by cell fitness rather than the inherent biology of the cells. These data show that, to reproducibly measure immunological biomarkers using cryopreserved PBMCs, minimal acceptable standards for cell fitness should be incorporated into the assay protocol.

Clinical predictors of early and late endoscopic recurrence following ileocolonic resection in Crohn's disease.

BACKGROUND AND AIM: Multiple factors are suggested to place Crohn's disease patients at risk of recurrence after ileocolic resection with conflicting associations. We aimed to identify clinical predictors of recurrence at first (early) and further (late) postoperative colonoscopy. METHODS: Crohn's disease patients undergoing ileocolic resection were prospectively recruited at six North American centers. Clinical data was collected and endoscopic recurrence was defined as Rutgeerts score ≥i2. A multivariable model was fitted to analyze variables independently associated with recurrence. RESULTS: A total of 365 patients undergoing 674 postoperative colonoscopies were included with a median age of 32 years, 189 (51.8%) were male and 37 (10.1%) non-Whites. Postoperatively, 133 (36.4%) used anti-TNF and 30 (8.2%) were smokers. At first colonoscopy, 109 (29.9%) had recurrence. Male gender (OR = 1.95, 95% CI 1.12 - 3.40), non-White ethnicity (OR = 2.48, 95% CI 1.09 - 5.63), longer interval between surgery and colonoscopy (OR = 1.09, 95% CI 1.002 - 1.18), and postoperative smoking (OR = 2.78, 95% CI 1.16 - 6.67) were associated with recurrence, while prophylactic anti-TNF reduced the risk (OR = 0.28, 95% CI 0.14 - 0.55). Postoperative anti-TNF prophylaxis had a protective effect on anti-TNF experienced patients but not on anti-TNF naïve patients. Among patients without recurrence at first colonoscopy, Rutgeerts score i1 was associated with subsequent recurrence (OR = 4.43, 95% CI 1.73 - 11.35). CONCLUSIONS: We identified independent clinical predictors of early and late Crohn's disease postoperative endoscopic recurrence. Clinical factors traditionally used for risk stratification failed to predict recurrence and need to be revised.

The Burden of Anemia Remains Significant over Time in Patients with Inflammatory Bowel Diseases at a Tertiary Referral Center.

BACKGROUND AND AIMS: Anemia is a common complication of inflammatory bowel diseases (IBD), as well as a predictor of poor outcomes. The aim of this study was to determine the prevalence of anemia over time and the management of moderate to severe anemia at a tertiary referral IBD center. METHODS: We retrospectively reviewed the occurrence of anemia at the time of referral or diagnosis and during follow-up at the McGill University Health Centre IBD center. Consecutive patients presenting with an outpatient visit between July and December 2016 and between December 2018 and March 2019 were included. Disease characteristics, biochemistry and medical management, including the need for intravenous iron therapy were recorded. RESULTS: 1,356 Crohn's disease (CD) and 1,293 ulcerative colitis (UC) patients [disease duration: 12 (IQR: 6-22) and 10 (IQR: 5-19) years respectively] were included. The prevalence of moderate to severe anemia at referral/diagnosis (15.4% and 8.5%) and during follow-up (11.1% and 8.1%) were higher in CD than in UC patients. In CD, previous resective surgery, perianal disease and elevated C-reactive protein (CRP) at assessment, while in UC steroid therapy, an elevated CRP and fecal calprotectin at assessment were associated with anemia in a multivariate analysis. Anemia improved by >2g/dL in 56.5% after 4-6 weeks (intravenous iron dose >1000 mg in 87% of patients). CONCLUSION: Anemia occurred frequently in this IBD cohort, at referral to the center and during follow-up, and contributes to the burden of IBD in referral populations. Most patients were assessed for anemia regularly and with accurate anemia workup; however, the targeted management of moderate to severe anemia was suboptimal.

Benefits of implementing a rapid access clinic in a high-volume inflammatory bowel disease center: Access, resource utilization and outcomes.

BACKGROUND: Emergency situations in inflammatory bowel diseases (IBD) put significant burden on both the patient and the healthcare system. AIM: To prospectively measure Quality-of-Care indicators and resource utilization after the implementation of the new rapid access clinic service (RAC) at a tertiary IBD center. METHODS: Patient access, resource utilization and outcome parameters were collected from consecutive patients contacting the RAC between July 2017 and March 2019 in this observational study. For comparing resource utilization and healthcare costs, emergency department (ED) visits of IBD patients with no access to RAC services were evaluated between January 2018 and January 2019. Time to appointment, diagnostic methods, change in medical therapy, unplanned ED visits, hospitalizations and surgical admissions were calculated and compared. RESULTS: 488 patients (Crohn's disease: 68.4%/ulcerative colitis: 31.6%) contacted the RAC with a valid medical reason. Median time to visit with an IBD specialist following the index contact was 2 d. Patients had objective clinical and laboratory assessment (C-reactive protein and fecal calprotectin in 91% and 73%). Fast-track colonoscopy/sigmoidoscopy was performed in 24.6% of the patients, while computed tomography/magnetic resonance imaging in only 8.1%. Medical therapy was changed in 54.4%. ED visits within 30 d following the RAC visit occurred in 8.8% (unplanned ED visit rate: 5.9%). Diagnostic procedures and resource utilization at the ED (n = 135 patients) were substantially different compared to RAC users: Abdominal computed tomography was more frequent (65.7%, P < 0.001), coupled with multiple specialist consults, more frequent hospital admission (P < 0.001), higher steroid initiation (P < 0.001). Average medical cost estimates of diagnostic procedures and services per patient was $403 CAD vs $1885 CAD comparing all RAC and ED visits. CONCLUSION: Implementation of a RAC improved patient care by facilitating easier access to IBD specific medical care, optimized resource utilization and helped avoiding ED visits and subsequent hospitalizations.

Metabolic effects of dietary cholesterol in an animal model of insulin resistance and hepatic steatosis.

Although the atherogenic role of dietary cholesterol has been well established, its diabetogenic potential and associated metabolic disturbances have not been reported. Diet-induced hamster models of insulin resistance and dyslipidemia were employed to determine lipogenic and diabetogenic effects of dietary cholesterol. Metabolic studies were conducted in hamsters fed diets rich in fructose (40%), fat (30%), and cholesterol (0.05-0.25%) (FFC) and other test diets. Short-term feeding of the FFC diet induced insulin resistance, glucose intolerance, hypertriglyceridemia, and hypercholesterolemia. Prolonged feeding (6-22 wk) of the FFC diet led to severe hepatic steatosis, glucose intolerance, and mild increases in fasting blood glucose, suggesting progression toward type 2 diabetes, but did not induce beta-cell dysfunction. Metabolic changes induced by the diet, including dyslipidemia and insulin resistance, were cholesterol concentration dependent and were only markedly induced on a high-fructose and high-fat dietary background. There were significant increases in hepatic and plasma triglyceride with FFC feeding, likely due to a 10- to 15-fold induction of hepatic stearoyl-CoA desaturase compared with chow levels (P < 0.03). Hepatic insulin resistance was evident based on reduced tyrosine phosphorylation of the insulin receptor-beta, IRS-1, and IRS-2 as well as increased protein mass of protein tyrosine phosphatase 1B. Interestingly, nuclear liver X receptor (LXR) target genes such as ABCA1 were upregulated on the FFC diet, and dietary supplementation with an LXR agonist (instead of dietary cholesterol) worsened dyslipidemia, glucose intolerance, and upregulation of target mRNA and proteins similar to that of dietary cholesterol. In summary, these data clearly implicate dietary cholesterol, synergistically acting with dietary fat and fructose, as a major determinant of the severity of metabolic disturbances in the hamster model. Dietary cholesterol appears to induce hepatic cholesterol ester and triglyceride accumulation, and diet-induced LXR activation (via cholesterol-derived oxysterols) may possibly be one key underlying mechanism.

Perceived Quality of Care is Associated with Disease Activity, Quality of Life, Work Productivity, and Gender, but not Disease Phenotype: A Prospective Study in a High-volume IBD Centre.

BACKGROUND AND AIMS: Measuring quality of care [QoC] in inflammatory bowel diseases [IBD] has become increasingly important, yet complex assessment of QoC from the patients' perspective is rare. We evaluated perceived QoC using the Quality of Care Through the Patient's Eyes-IBD [QUOTE-IBD] questionnaire, and investigated associations between QoC, disease phenotype, work productivity, and health-related quality of life [HRQoL] in a high-volume IBD centre. METHODS: Consecutive patients attending McGill University Health Centre [MUHC]-IBD Centre completed the QUOTE-IBD, Short Inflammatory Bowel Disease Questionnaire [SIBDQ], IBD-Control, and Work Productivity and Activity Impairment [WPAI] questionnaires. The QUOTE-IBD comprises 23 questions, each rated by a quality impact [QI] score. QI scores were calculated for the evaluation of IBD specialists, general practitioners [GPs], and hospital care. RESULTS: In all, 525 patients completed the questionnaire. Total QI scores for IBD specialists, GPs, and hospital care were 8.57, 8.70, and 8.33, respectively. The lowest QI scores were related to 'accessibility' for both IBD specialists and GPs. Female gender, current disease activity, poor HRQoL [SIBDQ score ≤50], and poor disease control [IBD-Control score <13] were associated with lower mean QI scores [p <0.001 for all]. Disease phenotype was not associated with QI scores in either Crohn's disease [CD] or ulcerative colitis [UC] [p = 0.69, p = 0.791, respectively]. An inverse correlation was found between total QI scores and work productivity loss [IBD specialist: p <0.001; GP: p = 0.004]. CONCLUSIONS: Overall patient satisfaction with QoC was good; however, improving patient accessibility to care is warranted. Disease phenotype was not associated with patient satisfaction, whereas female gender, current disease activity, HRQoL, and work productivity loss were associated with patients' quality assessment, underlining that perceived QoC could be partly subjective regarding disease control and quality of life.

Harmonization of quality of care in an IBD center impacts disease outcomes: Importance of structure, process indicators and rapid access clinic.

BACKGROUND AND AIMS: We aimed to evaluate the quality of care at a tertiary inflammatory bowel disease (IBD) center using quality of care indicators (QIs) including patient assessment strategy, monitoring, treatment decisions and outcomes. METHODS: We retrospectively reviewed the quality of care pre- and post-referral and during follow-up at the at the McGill University Health Center (MUHC) IBD center. Consecutive patients were included presenting with an outpatient visit ('index visit') between July and December 2016. Disease characteristics, biochemistry, imaging and endoscopy data, changes in medications, and vaccination profiles were captured. RESULTS: 1357 patients were included. At referral, a large proportion of patients were objectively re-evaluated (ileocolonoscopy: 79%, cross-sectional imaging: 39.3%, biomarkers: 89.9%, 81.9%). Therapeutic strategy was changed in 53.6% with 22.5% of patients starting biologics. Tight objective patient monitoring was applied during follow-up (colonoscopy: 79%, cross-sectional imaging: 61.8% were available at index visit; C-reactive protein: 78%, Faecal calprotectin: 37.6%, therapeutic drug monitoring: 16.3% were performed additionally). Maximum therapeutic step was biologicals in 48.8% of the patients, while only 6.6% of all patients were steroid dependent. Implementation of a rapid access clinic improved healthcare delivery. CONCLUSIONS: Our data support that tight monitoring was applied at the MUHC IBD center with a high emphasis on objective patient (re)evaluation, timely access and accelerated treatment strategy at referral and during follow-up.

High Adherence to Surveillance Guidelines in Inflammatory Bowel Disease Patients Results in Low Colorectal Cancer and Dysplasia Rates, While Rates of Dysplasia are Low Before the Suggested Onset of Surveillance.

BACKGROUND: Patients with Crohn's disease [CD] and ulcerative colitis [UC] are at increased risk for colorectal dysplasia [CRD] and colorectal cancer [CRC]. Adherence to CRC surveillance guidelines is reportedly low internationally. AIM: To evaluate surveillance practices at the tertiary IBD Center of the McGill University Health Center [MUHC] and to determine CRD/CRC incidence. METHODS: A representative inflammatory bowel disease cohort with at least 8 years of disease duration [or with primary sclerosing cholangitis] who visited the MUHC between July 1 and December 31, 2016 were included. Adherence to surveillance guidelines was compared to modified 2010 British Society of Gastroenterology guidelines. Incidence rates of CRC, high-grade dysplasia [HGD], low-grade dysplasia [LGD] and colorectal adenomas [CRA] were calculated based on pathology. RESULTS: In total, 1356 CD and UC patients (disease duration: 12 [interquartile range: 6-22) and 10 [interquartile range: 5-19] years) were identified. The surveillance cohort consisted of 680 patients [296 UC and 384 CD]. Adherence to surveillance guidelines was 76/82% in UC/colonic CD. An adequate number of biopsies were taken in 54/54% of UC/colonic CD patients. The incidence of CRC/HGD in UC and CD with colonic involvement was 19.5/58.5 and 25.1/37.6 per 100,000 patient-years, respectively. The incidence of dysplasia before 8 years of disease duration was low in both UC/CD [19.5 and 12.5/100,000 patient-years] with no CRC detected. The CRA rate was 30/38% in UC/colonic CD. CONCLUSION: High adherence to surveillance guidelines and low CRC and dysplasia, but not CRA rates were found, suggesting that adhering to updated, stratified, surveillance recommendations may result in low advanced neoplasia rates. The incidence of dysplasia before the start of surveillance was low.

Patients' perception of their involvement in shared treatment decision making: Key factors in the treatment of inflammatory bowel disease.

OBJECTIVES: This study aims to characterize the relationships between the quality of the information given by the physician, the involvement of the patient in shared decision making (SDM), and outcomes in terms of satisfaction and anxiety pertaining to the treatment of inflammatory bowel disease (IBD). METHODS: A Web survey was conducted among 200 Canadian patients affected with IBD. The theoretical model of SDM was adjusted using path analysis. SAS software was used for all statistical analyses. RESULTS: The quality of the knowledge transfer between the physician and the patient is significantly associated with the components of SDM: information comprehension, patient involvement and decision certainty about the chosen treatment. In return, patient involvement in SDM is significantly associated with higher satisfaction and, as a result, lower anxiety as regards treatment selection. CONCLUSIONS: This study demonstrates the importance of involving patients in shared treatment decision making in the context of IBD. PRACTICE IMPLICATIONS: Understanding shared decision making may motivate patients to be more active in understanding the relevant information for treatment selection, as it is related to their level of satisfaction, anxiety and adherence to treatment. This relationship should encourage physicians to promote shared decision making.

Exploring the Use of a Participative Design in the Early Development of a Predictive Test: The Importance of Physician Involvement.

In this study, we contribute to the personalized medicine and health care management literature by developing and testing a new participative design approach. We propose that involving gastroenterologists in the development of a predictive test to assist them in their clinical decision-making process for the treatment of inflammatory bowel diseases will increase the likelihood of their acceptance of the innovation. Based on data obtained from 6 focus groups across Canada from a total of 28 physicians, analyses reveal that current tools do not enable discriminating between treatment options to find the best fit for each patient. Physicians expect a new predictive tool to have the capability of showing clear reliability and significant benefits for the patient, while being accessible in a timely manner that facilitates clinical decisions. Physicians also insist on their key role in the implementation process, hence confirming the relevance and importance of participative designs in personalized medicine.

AMPK activation through mitochondrial regulation results in increased substrate oxidation and improved metabolic parameters in models of diabetes.

Modulation of mitochondrial function through inhibiting respiratory complex I activates a key sensor of cellular energy status, the 5'-AMP-activated protein kinase (AMPK). Activation of AMPK results in the mobilization of nutrient uptake and catabolism for mitochondrial ATP generation to restore energy homeostasis. How these nutrient pathways are affected in the presence of a potent modulator of mitochondrial function and the role of AMPK activation in these effects remain unclear. We have identified a molecule, named R419, that activates AMPK in vitro via complex I inhibition at much lower concentrations than metformin (IC50 100 nM vs 27 mM, respectively). R419 potently increased myocyte glucose uptake that was dependent on AMPK activation, while its ability to suppress hepatic glucose production in vitro was not. In addition, R419 treatment of mouse primary hepatocytes increased fatty acid oxidation and inhibited lipogenesis in an AMPK-dependent fashion. We have performed an extensive metabolic characterization of its effects in the db/db mouse diabetes model. In vivo metabolite profiling of R419-treated db/db mice showed a clear upregulation of fatty acid oxidation and catabolism of branched chain amino acids. Additionally, analyses performed using both (13)C-palmitate and (13)C-glucose tracers revealed that R419 induces complete oxidation of both glucose and palmitate to CO2 in skeletal muscle, liver, and adipose tissue, confirming that the compound increases mitochondrial function in vivo. Taken together, our results show that R419 is a potent inhibitor of complex I and modulates mitochondrial function in vitro and in diabetic animals in vivo. R419 may serve as a valuable molecular tool for investigating the impact of modulating mitochondrial function on nutrient metabolism in multiple tissues and on glucose and lipid homeostasis in diabetic animal models.

Insulin inhibition of apolipoprotein B mRNA translation is mediated via the PI-3 kinase/mTOR signaling cascade but does not involve internal ribosomal entry site (IRES) initiation.

Although insulin normally activates global mRNA translation, it has a specific inhibitory effect on translation of apolipoprotein B (apoB) mRNA. This suggests that insulin induces a unique signaling cascade that leads to specific inhibition of apoB mRNA translation despite global translational stimulation. Recent studies have revealed that insulin functions to regulate apoB mRNA translation through a mechanism involving the apoB mRNA 5' untranslated region (5' UTR). Here, we further investigate the role of downstream insulin signaling molecules on apoB mRNA translation, and the mechanism of apoB mRNA translation itself. Transfection studies in HepG2 cells expressing deletion constructs of the apoB 5' UTR showed that the cis-acting region responding to insulin was localized within the first 64 nucleotides. Experiments using chimeric apoB UTR-luciferase constructs transfected into HepG2 cells followed by treatment with wortmannin, a PI-3K inhibitor, and rapamycin, an mTOR inhibitor, showed that signaling via PI-3K and mTOR pathways is necessary for insulin-mediated inhibition of chimeric 5' UTR-luciferase expression. In vitro translation of chimeric cRNA confirmed that the effects observed were translational in nature. Furthermore, using RNA-EMSA we found that wortmannin pretreatment blocked insulin-mediated inhibition of the binding of RNA-binding factor(s), migrating near the 110 kDa marker, to the 5' UTR. Radiolabeling studies in HepG2 cells also showed that insulin-mediated control of the synthesis of endogenously expressed full length apoB100 is mediated via the PI-3K and mTOR pathways. Finally, using dual-cistronic luciferase constructs we demonstrate that apoB 5' UTR may have weak internal ribosomal entry (IRES) translation which is not affected by insulin stimulation, and may function to stimulate basal levels of apoB mRNA translation.