Accurate Classification of Pediatric Colonic Inflammatory Bowel Disease Subtype Using a Random Forest Machine Learning Classifier.

BACKGROUND: The pediatric inflammatory bowel disease (PIBD) classes algorithm was developed to bring consistency to labelling of colonic IBD, but labels are exclusively based on features atypical for ulcerative colitis (UC). AIM: The aim of the study was to develop an algorithm and identify features that discriminate between pediatric UC and colonic Crohn disease (CD). METHODS: Baseline clinical, endoscopic, radiologic, and histologic data, including the PIBD class features in 74 colonic IBD (56: UC, 18: colonic CD) patients were collected. The PIBD class features and additional features common to UC were used to perform initial clustering, using similarity network fusion (SNF). We trained a Random Forest (RF) classifier on the full dataset and used a leave-one-out approach to evaluate model accuracy. The top-features were used to build a new classifier, which we tested on 15 previously unused patients. We then performed clustering with SNF on the top RF features and assessed ability to discriminate between UC and colonic-CD independent of a supervised model. RESULTS: The initial SNF clustering with 58 patients demonstrated 2 groups: group 1 (n = 39, 90% UC) and group 2 (n = 19, 68% colonic-CD). Our RF classifier correctly labelled 97% of the 58 patients based on leave-one-out cross validation and identified the 7 most important features (3 histological and 4 endoscopic) to clinically distinguish these groups. We trained a new RF classifier with the top 7 features and found 100% accuracy in a set of 15 held-out patients. Finally, post hoc clustering with these 7 features revealed 2 groups of patients: group 1 (n = 55, 98% UC) and group 2 (n = 18, 94% colonic-CD). CONCLUSIONS: A combination of supervised and unsupervised analyses identified a short list of features, which consistently distinguish UC from colonic CD. Future directions include validation in other populations.

Differentiation of Colonic Inflammatory Bowel Disease: Re-examination of Paediatric Inflammatory Bowel Disease Classes Algorithm With Resected Colon As the Criterion Standard.

OBJECTIVES: Differentiation of Crohn disease (CD) from ulcerative colitis (UC) is challenging when inflammation is predominantly colonic. The paediatric inflammatory bowel disease (PIBD) classes algorithm was developed to bring consistency to labelling, but used physician-assigned diagnosis as the criterion standard. We aimed to reassess the PIBD classes using pathology of subsequently resected colon as the criterion standard. METHOD: Single-centre study of patients diagnosed with colonic IBD between 2002 and 2017 and subsequently treated with colectomy. Baseline pretreatment data were reviewed and the PIBD classes algorithm was independently applied by 2 reviewers to assign a label of UC/IBD-unclassified (IBD-U)/colonic-CD. Concordance between the algorithm-based, precolectomy clinical, and pathologic examination of resected colon diagnosis were assessed. Changes in diagnosis during postcolectomy follow-up were recorded. RESULTS: Sixty-two children underwent colectomy for medically refractory colonic IBD. Diagnosis based on pathologic review of resected colon CD:4;UC:56;IBDU:2. The clinical, PIBD classes algorithm, and colectomy diagnoses were concordant in 51 of 62 patients (81%, Fleiss kappa 0.48). Precolectomy clinical diagnosis was concordant with colectomy diagnosis in 58 of 62 patients (94%, weighted-kappa 0.65). The PIBD classes label was concordant with colectomy diagnosis in 51 of 62 patients (82%, weighted-kappa 0.38); resected colon pathology was typical of UC in 6 patients with PIBD classes label of IBD-U based on single class 2 feature and in 3 with PIBD classes label of CD based on single class 1 feature. CONCLUSIONS: Concordance of PIBD classes algorithm diagnosis applied before colectomy with a diagnostic label based on pathologic examination of a subsequently resected colon is only fair. Caution is needed in stringent application of colonic CD and IBD-U labels based on presence of single feature.

Feasibility and Performance of Elastin Trichrome as a Primary Stain in Colorectal Cancer Resection Specimens: Results of an Interobserver Variability Study.

Venous invasion (VI) is a powerful prognostic factor in colorectal cancer (CRC) that is widely underreported. The ability of elastin stains to improve VI detection is now recognized in several international CRC pathology protocols. However, concerns related to the cost and time required to perform and evaluate these stains in addition to routine hematoxylin and eosin (H&E) stains remains a barrier to their wider use. We therefore sought to determine whether an elastin trichrome (ET) stain could be used as a "stand-alone" stain in CRC resections, by comparing the sensitivity, accuracy, and reproducibility of detection of CAP-mandated prognostic factors using ET and H&E stains. Representative H&E- and ET-stained slides from 50 CRC resections, including a representative mix of stages and prognostic factors, were used to generate 2 study sets. Each case was represented by H&E slides in 1 study set and by corresponding ET slides from the same blocks in the other study set. Ten observers (3 academic gastrointestinal [GI] pathologists, 4 community pathologists, 3 fellows) evaluated each study set for CAP-mandated prognostic factors. ET outperformed H&E in the assessment of VI with respect to detection rates (50% vs. 28.6%; P<0.0001), accuracy (82% vs. 59%, P<0.0001), and reproducibility (k=0.554 vs. 0.394). No significant differences between ET and H&E were observed for other features evaluated. In a poststudy survey, most observers considered the ease and speed of assessment at least equivalent for ET and H&E for most prognostic factors, and felt that ET would be feasible as a stand-alone stain in practice. If validated by others, our findings support the use of ET, rather than H&E, as the primary stain for the evaluation of CRC resections.

Preoperative exposure to anti-tumor necrosis factor therapy in ulcerative colitis patients undergoing ileal pouch-anal anastomosis (IPAA) is not associated with histological fibrosis: A case control study.

BACKGROUND: We sought to determine whether preoperative exposure to anti-TNF therapy affects objective histological measures of fibrosis in the colorectum. METHODS: Ulcerative colitis (UC) patients who received infliximab as maintenance therapy pre IPAA surgery were identified and compared to anti-TNF-naïve matched controls by age, sex, BMI, disease duration, albumin levels, and post-operative leak outcome. Hematoxylin and eosin- (H&E) and trichrome-stained slides from the most distal, well-oriented, full-thickness section of colorectum from each patient's total colectomy specimen were evaluated. Blinded histopathological assessment of the degree of fibrosis was performed using a semi-quantitative pictorial scale. RESULTS: Histological fibrosis in 65 patients from the therapy group was compared to 65 patients from the matched control group. There were no statistically significant differences in the degree of fibrosis observed in any of the bowel layers. In the lamina propria, 29% of the control group and 28% of the treatment group had fibrosis scores ≥3. Fibrosis scores were higher in the submucosa, with both groups having 66% of patients showing scores ≥3. Similarly, in the region above the muscularis propria, 77% of the control group and 80% of the treatment group had fibrosis scores ≥3. In the subserosa, fibrosis scores were lower, with 25% of the control group and 32% of the treatment group having fibrosis scores ≥3. CONCLUSION: Resection specimens from UC patients treated with maintenance anti-TNF therapy who underwent IPAA surgery showed no significant differences in the degree of histologic fibrosis in any of the bowel layers compared to a matched control group.

Bifurcations and limit cycles in cytosolic yeast calcium.

Calcium homeostasis is a fundamental cellular process in yeast. The regulation of the cytosolic calcium concentration is required for volume preservation and to regulate many vital calcium dependent processes such as mating and response to stress. The homeostatic mechanism is often studied by applying calcium pulses: sharply changing the calcium concentration in the yeast environment and observing the cellular response. To address these experimental investigations, several mathematical models have been proposed to describe this response. In this article we demonstrate that a previously studied model for this response predicts the presence of limit point instabilities and limit cycles in the dynamics of the calcium homeostasis system. We discuss the ways in which such dynamic characteristics can be observed with luminometric techniques. We contrast these predictions with experimentally observed responses and find that the experiments reveal a number of features that are consistent with modeling predictions. In particular, we find that equilibrium cytosolic concentrations have a sharp change in behavior as pulse size changes in the micromolar range. We show that such change is consistent with the presence of limit point instabilities. Additionally, we find that the response of synchronized yeast cells to millimolar range pulses is non-monotonic in its late stages. This response has characteristics similar to those associated with limit cycles.

Prophylactic Total Gastrectomy: a Prospective Cohort Study of Long-Term Impact on Quality of Life.

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) syndrome is caused by germline mutations in the CDH1 gene and carries a lifetime gastric cancer risk of approximately 70 % in men and 56 % in women. Current consensus guidelines recommend that people of age ≥20 who harbor a CDH1 mutation undergo prophylactic total gastrectomy (PTG). However, the decision to proceed with a major visceral resection for prophylactic reasons may be difficult, especially since long-term outcomes are not well defined. We examined the decision-making process, physical symptoms, and psychosocial outcomes in adults who underwent PTG. METHODS: Participants completed pre- and post-operative questionnaires that included standardized measures of health-related quality of life (HRQOL), body image, psychological distress, regret, and decisional conflict. Those who declined surgery completed a questionnaire that measured decisional conflict and explored reasons for their choice. RESULTS: Forty of fifty (80 %) questionnaires distributed to 18 individuals were completed. In the 13 patients who underwent PTG, global HRQOL tended to decrease immediately post-operatively, climb to baseline by 6-12 months, then decrease again at 24 months. Body image and level of psychological distress remained relatively stable, and most patients expressed little decisional conflict or regret. All five individuals who declined surgery did so for practical reasons and would consider surgery in the future. CONCLUSIONS: While most patients do not experience negative psychosocial consequences following PTG, mild physical symptoms persist and may affect long-term HRQOL. The present study emphasizes the need for long-term follow-up of this unique population of survivors.

Maternal hypertension and neonatal outcome among small for gestational age infants.

OBJECTIVE: To determine whether maternal hypertension might improve perinatal outcome among small for gestational age (SGA) infants (< 10th percentile). METHODS: Our prospective cohort comprised 17 Canadian neonatal intensive care units (NICUs) and 3,244 SGA singletons. Multivariable regression was used to analyze the relation between maternal hypertension and each of the following: SNAP-II (Score of Neonatal Acute Physiology; ordinal regression) and neonatal survival and survival without severe intraventricular hemorrhage (logistic regression), adjusting for potential confounders. RESULTS: There were 698 (21.5%) neonates born to hypertensive mothers. Inversely associated with lower SNAP-II scores (healthier infant) were antenatal steroids (complete course: odds ratio [OR] 0.67, 95% confidence interval [CI] 0.54-0.83; incomplete: OR 0.71, 95% CI 0.56-0.88), lower gestational age (< 27 weeks: OR 0.06, 95% CI 0.05-0.08; 27-28 weeks: OR 0.11, 95% CI 0.07-0.17; 29-32 weeks: OR 0.28, 95% CI 0.23-0.35), 5-minute Apgar < 7 (OR 0.30, 95% CI 0.25-0.36), male gender (OR 0.80, 95% CI 0.70-0.92), and anomalies (OR 0.49, 95% CI 0.41-0.58). Maternal hypertension was associated with lower SNAP-II (healthier infant) (7.54 +/- 11.16 [hypertensive] versus 7.21 +/- 11.85 [normotensive]) on multivariable regression analysis (adjusted OR 1.25, 95% CI 1.05-1.49), as well as higher neonatal survival (93.0% versus 91.2%, and adjusted OR 1.9, 95% CI 1.2-3.0), but not survival without severe intraventricular hemorrhage (91.4% versus 87.0%, and adjusted OR 1.4, 95% CI 1.0-2.0), respectively. CONCLUSION: Among SGA neonates in NICU, maternal hypertension is associated with improved admission neonatal physiology and survival.

Surveillance patterns after curative-intent colorectal cancer surgery in Ontario.

BACKGROUND: Postoperative surveillance following curative-intent resection of colorectal cancer (CRC) is variably performed due to existing guideline differences and to the limited data supporting different strategies. OBJECTIVES: To examine population-based rates of surveillance imaging and endoscopy in patients in Ontario following curative-intent resection of CRC with no evidence of recurrence, as well as patient or disease factors that may predispose certain groups to more frequent versus less frequent surveillance; to provide insight to the care patients receive in the presence of conflicting guidelines, in efforts to help improve care of CRC survivors by identifying any potential underuse or overuse of particular surveillance modalities, or inequalities in access to surveillance. METHOD: A retrospective cohort study was conducted using data from the Ontario Cancer Registry and several linked databases. Ontario patients undergoing curative-intent CRC resection from 2003 to 2007 were identified, excluding patients with probable disease relapse. In the five-year period following surgery, the number of imaging and endoscopic examinations was determined. RESULTS: There were 4960 patients included in the study. Over the five-year postoperative period, the highest proportion of patients who underwent postoperative surveillance received the following number of tests for each modality examined: one to three abdominopelvic computed tomography (CT) scans (n=2073 [41.8%]); one to three abdominal ultrasounds (n=2443 [49.3%]); no chest CTs, one to three chest x-rays (n=2385 [48.1%]); and two endoscopies (n=1845 [37.2%]). Odds of not receiving any abdominopelvic imaging (CT or abdominal ultrasound) were higher in those who did not receive adjuvant chemotherapy (OR 6.99 [95% CI 5.26 to 9.35]) or those living in certain geographical areas, but were independent of age, sex and income. Nearly all patients (n=4473 [90.2%]) underwent ≥1 endoscopy at some point during the follow-up period. CONCLUSION: In contrast to findings from similar studies in other jurisdictions, most Ontario CRC survivors receive postoperative surveillance with imaging and endoscopy, and care is equitable across sociodemographic groups, although unexplained geographical variation in practice exists and warrants further investigation.

BTG2 antagonizes Pin1 in response to mitogens and telomere disruption during replicative senescence.

Cellular senescence limits the replicative capacity of normal cells and acts as an intrinsic barrier that protects against the development of cancer. Telomere shortening-induced replicative senescence is dependent on the ATM-p53-p21 pathway but additional genes likely contribute to senescence. Here, we show that the p53-responsive gene BTG2 plays an essential role in replicative senescence. Similar to p53 and p21 depletion, BTG2 depletion in human fibroblasts leads to an extension of cellular lifespan, and ectopic BTG2 induces senescence independently of p53. The anti-proliferative function of BTG2 during senescence involves its stabilization in response to telomere dysfunction followed by serum-dependent binding and relocalization of the cell cycle regulator prolyl isomerase Pin1. Pin1 inhibition leads to senescence in late-passage cells, and ectopic Pin1 expression rescues cells from BTG2-induced senescence. The neutralization of Pin1 by BTG2 provides a critical mechanism to maintain senescent arrest in the presence of mitogenic signals in normal primary fibroblasts.

The absolute configuration of (+)-(E)-4-phenylbut-3-ene-2-ol.

A derivative of (+)-(E)-4-phenylbut-3-ene-2-ol is shown by X-ray crystallography to be of (R) configuration, confirming the assumption in the literature that the absolute configuration of (+)-(E)-4-phenylbut-3-ene-2-ol is (R).