Identification of DNA methylation biomarkers with potential to predict response to neoadjuvant chemotherapy in triple-negative breast cancer

Neoadjuvant chemotherapy (NAC) is used to treat triple-negative breast cancer (TNBC) prior to resection. Biomarkers that accurately predict a patient’s response to NAC are needed to individualise therapy and avoid chemotoxicity from unnecessary chemotherapy. We performed whole-genome DNA methylation profiling on diagnostic TNBC biopsy samples from the Sequential Evaluation of Tumours Undergoing Preoperative (SETUP) NAC study. We found 9 significantly differentially methylated regions (DMRs) at diagnosis which were associated with response to NAC. We show that 4 of these DMRs are associated with TNBC overall survival (P < 0.05). Our results highlight the potential of DNA methylation biomarkers for predicting NAC response in TNBC.

Mechanical Learning for Prediction of Sepsis-Associated Encephalopathy

Objective: The study aims to develop a mechanical learning model as a predictive model for predicting the appearance of sepsis-associated encephalopathy (SAE).Materials and Methods: The prediction model was developed in a primary cohort of 2,028 sepsis patients from June 2001 to October 2012, retrieved from the Medical Information Mart for Intensive Care (MIMIC III) database. Least absolute shrinkage and selection operator (LASSO) regression model was used for data dimension reduction and feature selection. The model was developed using multivariable logistic regression analysis. The performance of the nomogram has been evaluated in terms of calibration, discrimination, and clinical utility.Results: There were nine particular features in septic patients that were significantly associated with SAE. Predictors of individualized prediction nomograms included age, rapid sequential evaluation of organ failure (qSOFA), and drugs including carbapenem antibiotics, quinolone antibiotics, steroids, midazolam, H2-antagonist, diphenhydramine hydrochloride, and heparin sodium injection. The area under the curve (AUC) was 0.743, indicating good discrimination. The prediction model showed calibration curves with minor deviations from the ideal predictions. Decision curve analysis (DCA) suggested that the nomogram was clinically useful.Conclusion: We propose a nomogram for the individualized prediction of SAE with satisfactory performance and clinical utility, which could aid the clinician in the early detection and management of SAE.

A Regional-Scale Landslide Early Warning System Based on the Sequential Evaluation Method: Development and Performance Analysis

A regional-scale landslide early warning system was developed in collaboration with a city government. The structure and distinctive features of the system are described in detail. This system employs the principles of the sequential evaluation method that consecutively applies three different evaluation stages: statistical, physically based, and geomorphological evaluations. Based on this method, the system determines five phases of warning levels with improved levels of certainty and credibility. In particular, the warning levels are systematically derived to enable the discrimination of slope failures and debris flows. To provide intuitive and pragmatic information regarding the warning capabilities of the system, a comprehensive performance analysis was conducted. Early warning level maps were generated and a historical landslide database was established for the study period from 2009 to 2016. As a result, 81% of historical slope failures and 86% of historical debris flows were correctly predicted by high-class warning levels. Miscellaneous details associated to the timing efficiency of warnings were also investigated. Most notably, five high-class warning level events and four landslide events were recorded for a study region during the eight-year period. The four landslide events were all successfully captured by four out of the five warning events.

Anxiety, Avoidance, and Sequential Evaluation

Anxiety disorders are characterized by a range of aberrations in the processing of and response to threat, but there is little clarity what core pathogenesis might underlie these symptoms. Here we propose that a particular set of unrealistically pessimistic assumptions can distort an agent’s behavior and underlie a host of seemingly disparate anxiety symptoms. We formalize this hypothesis in a decision-theoretic analysis of maladaptive avoidance and a reinforcement learning model, which shows how a localized bias in beliefs can formally explain a range of phenomena related to anxiety. The core observation, implicit in standard decision-theoretic accounts of sequential evaluation, is that the potential for avoidance should be protective: If danger can be avoided later, it poses less threat now. We show how a violation of this assumption—via a pessimistic, false belief that later avoidance will be unsuccessful—leads to a characteristic, excessive propagation of fear and avoidance to situations far antecedent of threat. This single deviation can explain a range of features of anxious behavior, including exaggerated threat appraisals, fear generalization, and persistent avoidance. Simulations of the model reproduce laboratory demonstrations of abnormal decision-making in anxiety, including in situations of approach–avoid conflict and planning to avoid losses. The model also ties together a number of other seemingly disjoint phenomena in anxious disorders. For instance, learning under the pessimistic bias captures a hypothesis about the role of anxiety in the later development of depression. The bias itself offers a new formalization of classic insights from the psychiatric literature about the central role of maladaptive beliefs about control and self-efficacy in anxiety. This perspective also extends previous computational accounts of beliefs about control in mood disorders, which neglected the sequential aspects of choice.