Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluation of empiric antibiotic de-escalation in febrile neutropenia

Introduction Up until 2010, the recommended duration of empiric broad-spectrum antibiotics for febrile neutropenia was until absolute neutrophil count (ANC) recovery. An updated guideline on the use of antimicrobial agents in neutropenic patients with cancer indicates that patients who have completed an appropriate treatment course of broad-spectrum antibiotics, with resolution of signs and symptoms of infection but persistent neutropenia, can be de-escalated to oral fluoroquinolone prophylaxis until ANC recovery. Methods The primary objective of this retrospective investigation was to evaluate the safety and efficacy of de-escalating broad-spectrum antibiotics in patients remaining neutropenic after at least 14 days of empiric broadspectrum antibiotics for febrile neutropenia compared to patients continuing broad-spectrum antibiotics until ANC recovery. Results There were 16 patients (61.5%) in the comparator group who met the primary endpoint of remaining afebrile and without escalation of antibiotics for at least 72 hours after 14 days of broad-spectrum antibiotics and 21 patients (80.7%) in the de-escalation group who met the primary endpoint of remaining afebrile and without reinitiation of broad-spectrum antibiotics for at least 72 hours after de-escalation to levofloxacin therapy (p = 0.11). Mean total duration of broad-spectrum antibiotic therapy was 23.5 ± 1.5 days in the comparator group versus 22.2 ± 1.43 days in the de-escalation group (p = 0.39). Conclusions Results of this investigation indicate that broad-spectrum antibiotics can be safely de-escalated to levofloxacin prophylaxis prior to ANC recovery in select patients. This practice may decrease the duration of broad-spectrum antibiotic exposure and associated complications.
Regulation of 3-Phosphoinositide–Dependent Protein Kinase 1 Activity by Homodimerization in Live Cells

Spatial and temporal regulation of the homodimerization of PDK1 modulates its activity. Sticking Together The “master kinase” phosphoinositide-dependent kinase 1 (PDK1) plays a central role in such processes as cellular proliferation and survival and has a wide range of targets, including protein kinase B (PKB). PDK1 is downstream of phosphatidylinositol 3-kinase (PI3K), and the generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) triggers the translocation of PDK1 and PKB to the plasma membrane, where PDK1 phosphorylates PKB. Although the mechanisms by which PDK1 activates its substrates are well studied, less is known about how the activity of PDK1 is regulated. Masters et al. used a combination of Förster resonance energy transfer (FRET)–based analysis of fluorescently tagged proteins in live cells, as well as computational modeling, to show that a subset of cytosolic PDK1 exists in a homodimeric form. Disruption of the homodimeric interface increased the association between PDK1 and PKB, and this and other evidence suggested that monomeric—rather than dimeric—PDK1 was the active form. Together, these data suggest that homodimerization of PDK1 regulates its activity. 3-Phosphoinositide–dependent kinase 1 (PDK1) plays a central role in regulating the activity of protein kinases that are essential for signaling; however, how PDK1 itself is regulated is largely unknown. We found that homodimerization of PDK1 is a spatially and temporally regulated mechanism for controlling PDK1 activity. We used Förster resonance energy transfer monitored by fluorescence lifetime imaging microscopy to observe PDK1 homodimerization in live cells. A pleckstrin homology (PH) domain–dependent, basal dimeric association of PDK1 was increased upon cell stimulation with growth factors; this association was prevented by a phosphatidylinositol 3-kinase inhibitor and by a mutation in, or a complete deletion of, the PH domain of PDK1. The distinct spatial distribution of PDK1 homodimers relative to that of heterodimers of PDK1 and protein kinase B (PKB), and the ability of monomeric mutants of PDK1 to phosphorylate PKB, suggested that the monomer was the active conformation. Mutation of the autophosphorylation residue threonine-513 to glutamate, which was predicted to destabilize the homodimer interface, enhanced the interaction between PDK1 and PKB and the activity of PKB. Through in vitro, time-resolved fluorescence intensity and anisotropy measurements, combined with existing crystal structures and computational molecular modeling, we determined the geometrical arrangement of the PDK1 homodimer. With this approach, we calculated the size of the population of PDK1 dimers in cells. This description of a previously uncharacterized regulatory mechanism for the activation of PDK1 offers possibilities for controlling PDK1 activity therapeutically.
Feature Distilled Tracking

Feature extraction and representation is one of the most important components for fast, accurate, and robust visual tracking. Very deep convolutional neural networks (CNNs) provide effective tools for feature extraction with good generalization ability. However, extracting features using very deep CNN models needs high performance hardware due to its large computation complexity, which prohibits its extensions in real-time applications. To alleviate this problem, we aim at obtaining small and fast-to-execute shallow models based on model compression for visual tracking. Specifically, we propose a small feature distilled network (FDN) for tracking by imitating the intermediate representations of a much deeper network. The FDN extracts rich visual features with higher speed than the original deeper network. To further speed-up, we introduce a shift-and-stitch method to reduce the arithmetic operations, while preserving the spatial resolution of the distilled feature maps unchanged. Finally, a scale adaptive discriminative correlation filter is learned on the distilled feature for visual tracking to handle scale variation of the target. Comprehensive experimental results on object tracking benchmark datasets show that the proposed approach achieves ${5\times }$ speed-up with competitive performance to the state-of-the-art deep trackers.
Fuzzy Finite Time Control for Switched Systems via Adding a Barrier Power Integrator

This paper concentrates on the study of finite time control for nonlinear switched systems. Based on a newly introduced adding a barrier integrator technique, a novel adaptive fuzzy control strategy is proposed for a class of nonlinear switched systems. Compared with the existing adaptive control methods, the proposed method has several distinguishing features. Finite time control: the proposed adaptive control method can solve the exact finite time control problem for the stabilization and some types of tracking issues. Namely, the errors will converge to zero in finite time. For a general tracking problem, the practical finite time control can be achieved. More general systems: the proposed method is suitable for high order nonlinear switched systems with arbitrary switching and unknown control gains. Some strict assumptions on the system dynamics are relaxed. Full state constraints: the proposed method can be utilized to deal with the full state constraints problem. Simple controller structure: the “explosion of the complexity” in the backstepping design is avoided. Singularity free design: the singularity problem is carefully handled during the whole design procedure. Examples are presented to illustrate the effectiveness of the proposed method.
Rationalizing the use of auxiliary label for oral oncology drugs

Objective The objective of this study is to develop a systematic approach to standardize the use of auxiliary labels for oral oncology drugs. Design The project was multi-phased: environmental scan of auxiliary labels used at six BC Cancer Agency centre pharmacies, develop guidelines to support auxiliary labels standardization, develop inclusion criteria for common warnings and standardize warnings based on guiding principles and evidence (Canadian Compendium of Pharmaceutical Specialties, BC Cancer Agency Cancer Drug Manual, British National Formulary, literature). Results Consistent auxiliary labels use was rare (7% of drugs). No explicit methodology for determining previous auxiliary labels use was identified. Guiding principles developed include auxiliary labels supplement counselling and drug-specific patient handouts; a maximum of four auxiliary labels (limited container size and alert fatigue); identify hazardous drugs with auxiliary labels; auxiliary labels not intended for universal warnings (e.g., keep out of reach of children); warnings prioritized by impact on storage, efficacy (e.g., administration instructions), toxicity (including interactions) and other clinical issues. Inclusion criteria were developed for warnings on pregnancy, crushing/chewing, taking with plenty of water, drowsiness/dizziness, alcohol, grapefruit juice, hazardous and sunlight exposure. First list of standardized auxiliary labels was completed in June 2014. Conclusion A systematic approach was developed to determine and prioritize auxiliary labels for oral oncology drugs. This has led to a standardized and more accurate labelling throughout the six BC Cancer Agency centres’ pharmacies.
CPS Operations and Risk Assessment in Child Abuse Cases Receiving Services: Initial Findings from the Pittsburgh Service Delivery Study

The Pittsburgh Service Delivery Study (PSDS) documents the service delivery experiences and outcomes of 90 families referred to Child Protective Services (CPS) following allegations of child physical or sexual abuse. In addition to describing the sample and methods, this article examines the psychometric characteristics of CPS caseworkers' risk assessment and subgroup differences in risk parameters. Findings revealed variability in the timeliness of worker decisions and good correspondence between sources for abuse classification. Risk assessment reports for a subset of cases were virtually unrelated to selected clinical functioning measures. Several risk parameters differentiated physically and sexually abusive families, which, collectively, correctly classified most of the cases. The findings provide a basis for understanding some of the operations of CPS and their role in the service delivery system.
Impact of a clinical pathway on appropriate empiric vancomycin use in cancer patients with febrile neutropenia

Objectives Febrile neutropenia management guidelines recommend the use of vancomycin as part of an empiric antimicrobial regimen when specific criteria are met. Often, vancomycin use among patients with febrile neutropenia is not indicated and may be over utilized for this indication. We sought to evaluate the impact of implementing a febrile neutropenia clinical pathway on empiric vancomycin use for febrile neutropenia and to identify predictors of vancomycin use when not indicated. Methods Adult febrile neutropenia patients who received initial therapy with an anti-pseudomonal beta-lactam with or without vancomycin were identified before (June 2008 to November 2010) and after (June 2012 to June 2013) pathway implementation. Patients were assessed for appropriateness of therapy based on whether the patient received vancomycin consistent with guideline recommendations. Using a comorbidity index used for risk assessment in high risk hematology/oncology patients, we evaluated whether specific comorbidities are associated with inappropriate vancomycin use in the setting of febrile neutropenia. Results A total of 206 patients were included in the pre-pathway time period with 35.9% of patients receiving vancomycin therapy that was inconsistent with the pathway. A total of 131 patients were included in the post-pathway time period with 11.4% of patients receiving vancomycin inconsistent with the pathway (p = 0.001). None of the comorbidities assessed, nor the comorbidity index score were found to be predictors of vancomycin use inconsistent with guideline recommendations. Conclusion Our study has demonstrated that implementation of a febrile neutropenia pathway can significantly improve adherence to national guideline recommendations with respect to empiric vancomycin utilization for febrile neutropenia.
System-Wide Temporal Characterization of the Proteome and Phosphoproteome of Human Embryonic Stem Cell Differentiation

Dynamic phosphorylation during stem cell differentiation may control recruitment of DNA methyltransferases to silence genes that maintain pluripotency. Dynamics of the Stem Cell Phosphoproteome Understanding the signaling events that control stem cell pluripotency and self-renewal and those governing differentiation should improve our ability to develop stem cell–based therapies. Rigbolt et al. performed global quantitative proteomic and phosphoproteomic analysis of human embryonic stem cells at five time points over 24 hours of nondirected (lineage-independent) differentiation initiated by two different paradigms. They identified a common core phosphoproteome associated with both differentiation protocols, discovered several temporal patterns of phosphorylation, and made predictions about changes in the activities of kinases during the differentiation period. DNA methyltransferases (DNMTs) exhibited dynamic changes in phosphorylation status that may influence their interaction with a promoter-bound protein complex, suggesting that the phosphorylation state of DNMTs may govern their recruitment to and thus silencing of target genes, such as those that promote pluripotency, during differentiation. To elucidate cellular events underlying the pluripotency of human embryonic stem cells (hESCs), we performed parallel quantitative proteomic and phosphoproteomic analyses of hESCs during differentiation initiated by a diacylglycerol analog or transfer to media that had not been conditioned by feeder cells. We profiled 6521 proteins and 23,522 phosphorylation sites, of which almost 50% displayed dynamic changes in phosphorylation status during 24 hours of differentiation. These data are a resource for studies of the events associated with the maintenance of hESC pluripotency and those accompanying their differentiation. From these data, we identified a core hESC phosphoproteome of sites with similar robust changes in response to the two distinct treatments. These sites exhibited distinct dynamic phosphorylation patterns, which were linked to known or predicted kinases on the basis of the matching sequence motif. In addition to identifying previously unknown phosphorylation sites on factors associated with differentiation, such as kinases and transcription factors, we observed dynamic phosphorylation of DNA methyltransferases (DNMTs). We found a specific interaction of DNMTs during early differentiation with the PAF1 (polymerase-associated factor 1) transcriptional elongation complex, which binds to promoters of the pluripotency and known DNMT target genes encoding OCT4 and NANOG, thereby providing a possible molecular link for the silencing of these genes during differentiation.
Stability and Stabilization of T–S Fuzzy Systems With Time-Varying Delays via Delay-Product-Type Functional Method

This paper is concerned with the stability and stabilization problems of T–S fuzzy systems with time-varying delays. The purpose is to develop a new state-feedback controller design method with less conservatism. First, a novel Lyapunov–Krasovskii functional is constructed by combining delay-product-type functional method together with the state vector augmentation. By utilizing Wirtinger-based integral inequality and an extended reciprocally convex matrix inequality, a less conservative delay-dependent stability condition is developed. Then, the corresponding controller design method for the closed-loop delayed fuzzy system is derived based on parallel distributed compensation scheme. Finally, two classic numerical examples are given to show the effectiveness and merits of the proposed approaches.
Multicenter study of environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in 48 Canadian hospitals

Context Oncology workers are occupationally exposed to antineoplastic drugs. This exposure can induce adverse health effects. In order to reduce their exposure, contamination on surfaces should be kept as low as possible. Objectives To monitor environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in oncology pharmacy and patient care areas in Canadian hospitals. To describe the impact of some factors that may limit contamination. Methods This is a descriptive study. Twelve standardized sites were sampled in each participating center (six in the pharmacy and six in patient care areas). Samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by ultra-performance liquid chromatography tandem mass spectrometry technology. Descriptive statistical analyses were done and results were compared with a Kolmogorov–Smirnov test for independent samples. Results In 2015, 48 hospitals participated in this study (48/202, 24%). Overall, 34% (181/525) of the samples were positive for cyclophosphamide, 8% (41/525) for ifosfamide, and 6% (31/525) for methotrexate. The 75th percentile value of cyclophosphamide surface concentration was 6.9 pg/cm2. For ifosfamide and methotrexate, they were lower than the limit of detection. Centers who prepared more antineoplastic drugs per year and centers who used more cyclophosphamide per year showed significantly higher surface contamination (p < 0.0001). Over the years, we observed a reduction in surface contamination. Conclusion In comparison with other multicenter studies that were conducted in Canada, the concentration of antineoplastic drugs measured on surfaces is decreasing. Regular environmental monitoring is a good practice in order to maintain contamination as low as reasonably achievable.
A new learning approach for fuzzy cognitive maps based on system performance indicators

Fuzzy cognitive map (FCM) is a simple and user friendly tool for modeling complex systems. It is described by the set of the concepts and the connections between them. FCM can be initialized based on expert knowledge or automatic constructed with the use of learning algorithms. Most learning methods focus on data error and the structure of the resulting model significantly differs from the reference object. This paper introduces a new multi-objective evolutionary approach for fuzzy cognitive maps learning based on system performance indicators. The proposed solution allows to select the most significant connections in terms of direct and indirect influence between concepts and obtain FCM models more similar to the reference structures. This approach was analyzed with the use of Elite Genetic Algorithm (EGA) and Individually Directional Evolutionary Algorithm (IDEA). Comparative analysis of the proposed methodology with the standard approach of FCMs learning was performed with the use of synthetic and real-life data. The obtained results show that the proposed approach based on system performance indicators outperforms the standard methodology focused only in data error.
Crowdsourcing Network Inference: The DREAM Predictive Signaling Network Challenge

By aggregating the efforts of the research community, comprehensive and accurate inference of signaling networks may become achievable. Computational analyses of systematic measurements on the states and activities of signaling proteins (as captured by phosphoproteomic data, for example) have the potential to uncover uncharacterized protein-protein interactions and to identify the subset that are important for cellular response to specific biological stimuli. However, inferring mechanistically plausible protein signaling networks (PSNs) from phosphoproteomics data is a difficult task, owing in part to the lack of sufficiently comprehensive experimental measurements, the inherent limitations of network inference algorithms, and a lack of standards for assessing the accuracy of inferred PSNs. A case study in which 12 research groups inferred PSNs from a phosphoproteomics data set demonstrates an assessment of inferred PSNs on the basis of the accuracy of their predictions. The concurrent prediction of the same previously unreported signaling interactions by different participating teams suggests relevant validation experiments and establishes a framework for combining PSNs inferred by multiple research groups into a composite PSN. We conclude that crowdsourcing the construction of PSNs—that is, outsourcing the task to the interested community—may be an effective strategy for network inference.
A New Biometric Technology Based on Mouse Dynamics

In this paper, we introduce a new form of behavioral biometrics based on mouse dynamics, which can be used in different security applications. We develop a technique that can be used to model the behavioral characteristics from the captured data using artificial neural networks. In addition, we present an architecture and implementation for the detector, which cover all the phases of the biometric data flow including the detection process. Experimental data illustrating the experiments conducted to evaluate the accuracy of the proposed detection technique are presented and analyzed. Specifically, three series of experiments are conducted. The main experiment, in which 22 participants are involved, reproduces real operating conditions in computing systems by giving participants an individual choice of operating environments and applications; 284 hours of raw mouse data are collected over 998 sessions, with an average of 45 sessions per user. The two other experiments, involving seven participants, provided a basis for studying the confounding factors arising from the main experiment by fixing the environment variables. In the main experiment, the performance results presented using receiver operating characteristic (ROC) curves and a confusion matrix yield at the crossover point (that is, the threshold set for an equal error rate) a false acceptance rate (FAR) of 2.4649 percent and a false rejection rate (FRR) of 2.4614 percent.
Nucleolar Localization of a Netrin-1 Isoform Enhances Tumor Cell Proliferation

A nuclear-localized isoform of netrin may enhance ribosome biogenesis to promote cancer growth. Nucleolar Netrin Ribosomes are the cellular sites for protein synthesis, and ribosomal RNA is transcribed in nuclear structures called nucleoli. The higher proliferation rate of tumor cells requires an increased rate of protein synthesis, and enhancing the rates of ribosomal RNA transcription and the production of ribosomes confers a growth advantage. Delloye-Bourgeois et al. characterized a truncated isoform of netrin-1 called ΔN-netrin-1 that, unlike the full-length form, was not secreted but instead localized to nucleoli where it interacted with proteins involved in ribosomal RNA transcription. Overexpression of ΔN-netrin-1 increased the cytoplasmic pool of ribosomes, proliferation of cultured cells, and tumor growth in an in vivo model. ΔN-netrin-1 was also detected in some cancer cell lines and human cancers. The current antitumor agents targeting the full-length netrin-1 isoform cannot enter cells and, thus, would likely not affect the pro-tumor activity of nucleolar ΔN-netrin-1. Netrin-1 displays proto-oncogenic activity in several cancers, which is thought to be due to the ability of this secreted cue to stimulate survival when bound to its receptors. We showed that in contrast to full-length, secreted netrin-1, some cancer cells produced a truncated intranuclear form of netrin-1 (ΔN-netrin-1) through an alternative internal promoter. Because of a nucleolar localization signal located in its carboxyl terminus, ΔN-netrin-1 was targeted to the nucleolus, where it interacted with nucleolar proteins, affected nucleolar ultrastructure, and interacted with the promoters of ribosomal genes. Moreover, ΔN-netrin-1 stimulated cell proliferation in vitro and tumor growth in vivo. Thus, some cancer cells produce not only a full-length, secreted form of netrin-1 that promotes cell survival but also a truncated netrin-1 that stimulates cell proliferation, potentially by enhancing ribosome biogenesis.