An integrative computational model for intestinal tissue renewal

Objectives\ud \ud The luminal surface of the gut is lined with a monolayer of epithelial cells that acts as a nutrient absorptive engine and protective barrier. To maintain its integrity and functionality, the epithelium is renewed every few days. Theoretical models are powerful tools that can be used to test hypotheses concerning the regulation of this renewal process, to investigate how its dysfunction can lead to loss of homeostasis and neoplasia, and to identify potential therapeutic interventions. Here we propose a new multiscale model for crypt dynamics that links phenomena occurring at the subcellular, cellular and tissue levels of organisation.\ud \ud Methods\ud \ud At the subcellular level, deterministic models characterise molecular networks, such as cell-cycle control and Wnt signalling. The output of these models determines the behaviour of each epithelial cell in response to intra-, inter- and extracellular cues. The modular nature of the model enables us to easily modify individual assumptions and analyse their effects on the system as a whole.\ud \ud Results\ud \ud We perform virtual microdissection and labelling-index experiments, evaluate the impact of various model extensions, obtain new insight into clonal expansion in the crypt, and compare our predictions with recent mitochondrial DNA mutation data. \ud \ud Conclusions\ud \ud We demonstrate that relaxing the assumption that stem-cell positions are fixed enables clonal expansion and niche succession to occur. We also predict that the presence of extracellular factors near the base of the crypt alone suffices to explain the observed spatial variation in nuclear beta-catenin levels along the crypt axis

The Recognizability and Localizability of Auditory Alarms: Setting Global Medical Device Standards.

Objective Four sets of eight audible alarms matching the functions specified in IEC 60601-1-8 were designed using known principles from auditory cognition with the intention that they would be more recognizable and localizable than those currently specified in the standard. Background The audible alarms associated with IEC 60601-1-8, a global medical device standard, are known to be difficult to learn and retain, and there have been many calls to update them. There are known principles of design and cognition that might form the basis of more readily recognizable alarms. There is also scope for improvement in the localizability of the existing alarms. Method Four alternative sets of alarms matched to the functions specified in IEC 60601-1-8 were tested for recognizability and localizability and compared with the alarms currently specified in the standard. Results With a single exception, all prototype sets of alarms outperformed the current IEC set on both recognizability and localizability. Within the prototype sets, auditory icons were the most easily recognized, but the other sets, using word rhythms and simple acoustic metaphors, were also more easily recognized than the current alarms. With the exception of one set, all prototype sets were also easier to localize. Conclusion Known auditory cognition and perception principles were successfully applied to an existing audible alarm problem. Application This work constitutes the first (benchmarking) phase of replacing the alarms currently specified in the standard. The design principles used for each set demonstrate the relative ease with which different alarm types can be recognized and localized

Risk of Bowel Obstruction in Patients Undergoing Neoadjuvant Chemotherapy for High-risk Colon Cancer

Objective: This study aimed to identify risk criteria available before the point of treatment initiation that can be used to stratify the risk of obstruction in patients undergoing neoadjuvant chemotherapy (NAC) for high-risk colon cancer. Background: Global implementation of NAC for colon cancer, informed by the FOxTROT trial, may increase the risk of bowel obstruction. Methods: A case-control study, nested within an international randomized controlled trial (FOxTROT; ClinicalTrials.gov: NCT00647530). Patients with high-risk operable colon cancer (radiologically staged T3-4 N0-2 M0) that were randomized to NAC and developed large bowel obstruction were identified. First, clinical outcomes were compared between patients receiving NAC in FOxTROT who did and did not develop obstruction. Second, obstructed patients (cases) were age-matched and sex-matched with patients who did not develop obstruction (controls) in a 1:3 ratio using random sampling. Bayesian conditional mixed-effects logistic regression modeling was used to explore clinical, radiologic, and pathologic features associated with obstruction. The absolute risk of obstruction based on the presence or absence of risk criteria was estimated for all patients receiving NAC. Results: Of 1053 patients randomized in FOxTROT, 699 received NAC, of whom 30 (4.3%) developed obstruction. Patients underwent care in European hospitals including 88 UK, 7 Danish, and 3 Swedish centers. There was more open surgery (65.4% vs 38.0%, P=0.01) and a higher pR1 rate in obstructed patients (12.0% vs 3.8%, P=0.004), but otherwise comparable postoperative outcomes. In the case-control–matched Bayesian model, 2 independent risk criteria were identified: (1) obstructing disease on endoscopy and/or being unable to pass through the tumor [adjusted odds ratio: 9.09, 95% credible interval: 2.34–39.66] and stricturing disease on radiology or endoscopy (odds ratio: 7.18, 95% CI: 1.84–32.34). Three risk groups were defined according to the presence or absence of these criteria: 63.4% (443/698) of patients were at very low risk (10%). Conclusions: Safe selection for NAC for colon cancer can be informed by using 2 features that are available before treatment initiation and identifying a small number of patients with a high risk of preoperative obstruction