bluuebunny/crossref_metadata_2025 huggingface dataset:
Building an Ambulatory Safety Program at an Academic Health System
Authors: Desai Sonali , Fiumara Karen , Kachalia Allen
Published: April 2019

Background

Patient safety has traditionally focused on the inpatient setting; however, there is an increased awareness of ambulatory safety risk. However, successful strategies and programs to mitigate risk in the ambulatory setting are lacking.

Program

In 2012, we started building a multidisciplinary ambulatory safety program at an academic health system. Our team was composed of clinical, administrative, and patient safety membership. Based on organizational needs, our program initially focused on the following: (1) safety reporting, (2) safety culture measurement, (3) medication safety, and (4) test result management.

What We Did

We were able to develop initiatives around safety reporting, safety culture survey administration, and medication safety and begin to work on test result management. Internal metrics were developed to measure performance and to drive improvement.

Safety Reporting

When evaluating our ambulatory safety reports, we discovered that less than one-third of staff filing safety reports requested feedback. From 2013 to 2018, we tested various strategies to increase the rates of feedback to staff and ultimately found that a decentralized process that was supported by the ambulatory safety program could achieve rates of feedback of 90%.

Safety Culture Measurement

We administered the Agency for Healthcare Research and Quality Medical Office Survey in 2012, 2014, and 2016, achieving a more than 70% response rate across 70 unique ambulatory areas. Data from these surveys were shared with senior hospital leadership, local departmental directors, and managers and ultimately with frontline staff focusing on two key survey areas: communication openness and communication about error.

Medication Safety

From 2012 to 2014, our rates of ambulatory medication reconciliation increased to more than 90% in both primary care and specialty practices in our homegrown electronic medical record system. From 2015 to 2016, rates of ambulatory medication reconciliation in our new vendor-based electronic medical record were 73% as of August 2017.

Conclusions

We were able to build an infrastructure to focus and support ambulatory safety efforts on safety reporting, safety culture change, and medication reconciliation with a team dedicated to ambulatory-focused safety risks and encountered many challenges along the way. Currently, we are expanding our program to concentrate on test result follow-up to prevent missed and delayed diagnosis and medication error reduction.
Effects of an Intensive Discharge Intervention on Medication Adherence, Glycemic Control, and Readmission Rates in Patients With Type 2 Diabetes
Authors: Magny-Normilus Cherlie , Nolido Nyryan V. , Borges Jorge C. , Brady Maureen , Labonville Stephanie , Williams Deborah , Soukup Jane , Lipsitz Stuart , Hudson Margo , Schnipper Jeffrey L.
Published: April 2019

Objectives

Patients with diabetes are at particularly high risk for adverse outcomes after hospitalization. The goals of this study were to design, implement, and evaluate a multipronged transitional care intervention among hospitalized patients with diabetes.

Methods

We randomly assigned inpatients likely to be discharged home on insulin to an intensive transitional care intervention or usual care. The primary outcome was 90-day postdischarge insulin adherence, using prescription refill information to calculate a medication possession ratio. Unadjusted analyses were conducted using Wilcoxon rank sum; adjusted analyses used multivariable linear regression and weighted propensity scoring methods, with general estimating equations to account for clustering by admitting physician.

Results

One hundred eighty patients participated. The mean (SD) medication possession ratio to all insulin types was 84.5% (22.6) among intervention and 76.4% (25.1) among usual care patients (difference = 8.1, 95% confidence interval = −1.0 to 17.2, P = 0.06), with a smaller difference for adherence to all medications (86.3% versus 82.0%). A1c levels decreased in both groups but was larger in the intervention arm (1.09 and 0.11, respectively) (difference = −0.98, 95% confidence interval = −2.03 to −0.07, P = 0.04). Differences between study arms were not significant for rates of hypoglycemic episodes, 30-day readmissions, or emergency department visits. In adjusted/clustered analyses, the difference in A1c reduction remained statistically significant, whereas differences in all other outcomes remained nonsignificant.

Conclusions

The intervention was associated with improvements in glycemic control, with nonsignificant trends toward greater medication adherence. Further research is needed to optimize and successfully implement interventions to improve patient safety and health outcomes during care transitions.
The Mental Health Trigger Tool: Development and Testing of a Specialized Trigger Tool for Mental Health Settings
Authors: Sajith Sreedharan Geetha , Fung Daniel Shuen Sheng , Chua Hong Choon
Published: April 2019

Objective

Tools generally used in measuring patient safety incidents in general healthcare settings are not considered suitable for mental health settings. The aim of this study was to develop and evaluate a specialized trigger tool for mental health settings that could detect both traditionally defined adverse events (AEs) and other mental health–related patient safety incidents (MHPSIs).

Methods

We first defined and categorized AEs and MHPSIs based on existing literature and then developed a trigger list, initially consisting of 50 items, which was subsequently reduced to 25 items after a pilot study. We then explored the properties of this final 25-item trigger tool, the Mental Health Trigger Tool (MHTT), through a retrospective review of 515 patient records with a two-stage review process similar to Global Trigger Tool methodology. We used findings of an alternative method of review which consisted of page-to-page reviews of patient records in the analysis of properties of MHTT.

Results

Using the MHTT, at least one AE was identified in 98 patient records (19%) and at least one MHPSI was identified in 58 patient records (11%). The MHTT had a sensitivity of 98.6% and its specificity was 100%. The probability of finding an AE/MHPSI when any trigger was detected in a patient record with MHTT was 33.8% and that of individual triggers ranged from 0% to 100%.

Conclusions

The MHTT may offer an effective, practical, and easy-to-use method in identifying and measuring safety incidents in mental health settings.
A brief history of liquid computers
Authors: Adamatzky Andrew
Published: April 2019

A substrate does not have to be solid to compute. It is possible to make a computer purely from a liquid. I demonstrate this using a variety of experimental prototypes where a liquid carries signals, actuates mechanical computing devices and hosts chemical reactions. We show hydraulic mathematical machines that compute functions based on mass transfer analogies. I discuss several prototypes of computing devices that employ fluid flows and jets. They are fluid mappers, where the fluid flow explores a geometrically constrained space to find an optimal way around, e.g. the shortest path in a maze, and fluid logic devices where fluid jet streams interact at the junctions of inlets and results of the computation are represented by fluid jets at selected outlets. Fluid mappers and fluidic logic devices compute continuously valued functions albeit discretized. There is also an opportunity to do discrete operation directly by representing information by droplets and liquid marbles (droplets coated by hydrophobic powder). There, computation is implemented at the sites, in time and space, where droplets collide one with another. The liquid computers mentioned above use liquid as signal carrier or actuator: the exact nature of the liquid is not that important. What is inside the liquid becomes crucial when reaction–diffusion liquid-phase computing devices come into play: there, the liquid hosts families of chemical species that interact with each other in a massive-parallel fashion. I shall illustrate a range of computational tasks, including computational geometry, implementable by excitation wave fronts in nonlinear active chemical medium. The overview will enable scientists and engineers to understand how vast is the variety of liquid computers and will inspire them to design their own experimental laboratory prototypes.

This article is part of the theme issue ‘Liquid brains, solid brains: How distributed cognitive architectures process information’.
Surface curvature guides early construction activity in mound-building termites
Authors: Calovi Daniel S. , Bardunias Paul , Carey Nicole , Scott Turner J. , Nagpal Radhika , Werfel Justin
Published: April 2019

Termite colonies construct towering, complex mounds, in a classic example of distributed agents coordinating their activity via interaction with a shared environment. The traditional explanation for how this coordination occurs focuses on the idea of a ‘cement pheromone’, a chemical signal left with deposited soil that triggers further deposition. Recent research has called this idea into question, pointing to a more complicated behavioural response to cues perceived with multiple senses. In this work, we explored the role of topological cues in affecting early construction activity in
Macrotermes
. We created artificial surfaces with a known range of curvatures, coated them with nest soil, placed groups of major workers on them and evaluated soil displacement as a function of location at the end of 1 h. Each point on the surface has a given curvature, inclination and absolute height; to disambiguate these factors, we conducted experiments with the surface in different orientations. Soil displacement activity is consistently correlated with surface curvature, and not with inclination nor height. Early exploration activity is also correlated with curvature, to a lesser degree. Topographical cues provide a long-term physical memory of building activity in a manner that ephemeral pheromone labelling cannot. Elucidating the roles of these and other cues for group coordination may help provide organizing principles for swarm robotics and other artificial systems.

This article is part of the theme issue ‘Liquid brains, solid brains: How distributed cognitive architectures process information’.
Statistical physics of liquid brains
Authors: Piñero Jordi , Solé Ricard
Published: April 2019

Liquid neural networks (or ‘liquid brains’) are a widespread class of cognitive living networks characterized by a common feature: the agents (ants or immune cells, for example) move in space. Thus, no fixed, long-term agent-agent connections are maintained, in contrast with standard neural systems. How is this class of systems capable of displaying cognitive abilities, from learning to decision-making? In this paper, the collective dynamics, memory and learning properties of liquid brains is explored under the perspective of statistical physics. Using a comparative approach, we review the generic properties of three large classes of systems, namely: standard neural networks (solid brains), ant colonies and the immune system. It is shown that, despite their intrinsic physical differences, these systems share key properties with standard neural systems in terms of formal descriptions, but strongly depart in other ways. On one hand, the attractors found in liquid brains are not always based on connection weights but instead on population abundances. However, some liquid systems use fluctuations in ways similar to those found in cortical networks, suggesting a relevant role for criticality as a way of rapidly reacting to external signals.

This article is part of the theme issue ‘Liquid brains, solid brains: How distributed cognitive architectures process information’.
Modular structure within groups causes information loss but can improve decision accuracy
Authors: Kao Albert B. , Couzin Iain D.
Published: April 2019

Many animal groups exhibit signatures of persistent internal modular structure, whereby individuals consistently interact with certain groupmates more than others. In such groups, information relevant to a collective decision may spread unevenly through the group, but how this impacts the quality of the resulting decision is not well understood. Here, we explicitly model modularity within animal groups and examine how it affects the amount of information represented in collective decisions, as well as the accuracy of those decisions. We find that modular structure necessarily causes a loss of information, effectively silencing the input from a fraction of the group. However, the effect of this information loss on collective accuracy depends on the informational environment in which the decision is made. In simple environments, the information loss is detrimental to collective accuracy. By contrast, in complex environments, modularity tends to improve accuracy. This is because small group sizes typically maximize collective accuracy in such environments, and modular structure allows a large group to behave like a smaller group (in terms of its decision-making). These results suggest that in naturalistic environments containing correlated information, large animal groups may be able to exploit modular structure to improve decision accuracy while retaining other benefits of large group size.

This article is part of the theme issue ‘Liquid brains, solid brains: How distributed cognitive architectures process information’.
The computational stance in biology
Authors: Wood C. C.
Published: April 2019

The goal of this article is to call attention to, and to express caution about, the extensive use of computation as an explanatory concept in contemporary biology. Inspired by Dennett's ‘intentional stance’ in the philosophy of mind, I suggest that a ‘computational stance’ can be a productive approach to evaluating the value of computational concepts in biology. Such an approach allows the value of computational ideas to be assessed without being diverted by arguments about whether a particular biological system is ‘actually computing’ or not. Because there is sufficient difference of agreement among computer scientists about the essential elements that constitute computation, any doctrinaire position about the application of computational ideas seems misguided. Closely related to the concept of computation is the concept of information processing. Indeed, some influential computer scientists contend that there is no fundamental difference between the two concepts. I will argue that despite the lack of widely accepted, general definitions of information processing and computation: (1) information processing and computation are not fully equivalent and there is value in maintaining a distinction between them and (2) that such value is particularly evident in applications of information processing and computation to biology.

This article is part of the theme issue ‘Liquid brains, solid brains: How distributed cognitive architectures process information’.
The brain: a concept in flux
Authors: Pagán Oné R.
Published: April 2019

One of the most important aspects of the scientific endeavour is the definition of specific concepts as precisely as possible. However, it is also important not to lose sight of two facts: (i) we divide the study of nature into manageable parts in order to better understand it owing to our limited cognitive capacities and (ii) definitions are inherently arbitrary and heavily influenced by cultural norms, language, the current political climate, and even personal preferences, among many other factors. As a consequence of these facts, clear-cut definitions, despite their evident importance, are oftentimes quite difficult to formulate. One of the most illustrative examples about the difficulty of articulating precise scientific definitions is trying to define the concept of a brain. Even though the current thinking about the brain is beginning to take into account a variety of organisms, a vertebrocentric bias still tends to dominate the scientific discourse about this concept. Here I will briefly explore the evolution of our ‘thoughts about the brain’, highlighting the difficulty of constructing a universally (or even a generally) accepted formal definition of it and using planarians as one of the earliest examples of organisms proposed to possess a ‘traditional’, vertebrate-style brain. I also suggest that the time is right to attempt to expand our view of what a brain is, going beyond exclusively structural and taxa-specific criteria. Thus, I propose a classification that could represent a starting point in an effort to expand our current definitions of the brain, hopefully to help initiate conversations leading to changes of perspective on how we think about this concept.

This article is part of the theme issue ‘Liquid brains, solid brains: How distributed cognitive architectures process information’.
Regulatory network-based imputation of dropouts in single-cell RNA sequencing data
Authors: Leote Ana Carolina , Wu Xiaohui , Beyer Andreas
Published: April 2019

Single-cell RNA sequencing (scRNA-seq) methods are typically unable to quantify the expression levels of all genes in a cell, creating a need for the computational prediction of missing values (‘dropout imputation’). Most existing dropout imputation methods are limited in the sense that they exclusively use the scRNA-seq dataset at hand and do not exploit external gene-gene relationship information. Further, it is unknown if all genes equally benefit from imputation or which imputation method works best for a given gene.

Here, we show that a transcriptional regulatory network learned from external, independent gene expression data improves dropout imputation. Using a variety of human scRNA-seq datasets we demonstrate that our network-based approach outperforms published state-of-the-art methods. The network-based approach performs particularly well for lowly expressed genes, including cell-type-specific transcriptional regulators. Further, the cell-to-cell variation of 12.6% to 48.2% of the genes could not be adequately imputed by any of the methods that we tested. In those cases gene expression levels were best predicted by the mean expression across all cells, i.e. assuming no measurable expression variation between cells. These findings suggest that different imputation methods are optimal for different genes. We thus implemented an R-package called ADImpute (available via Bioconductor https://bioconductor.org/packages/release/bioc/html/ADImpute.html) that automatically determines the best imputation method for each gene in a dataset.

Our work represents a paradigm shift by demonstrating that there is no single best imputation method. Instead, we propose that imputation should maximally exploit external information and be adapted to gene-specific features, such as expression level and expression variation across cells.

Author summary

Single-cell RNA-sequencing (scRNA-seq) allows for gene expression to be quantified in individual cells and thus plays a critical role in revealing differences between cells within tissues and characterizing them in healthy and pathological conditions. Because scRNA-seq captures the RNA content of individual cells, lowly expressed genes, for which few RNA molecules are present in the cell, are easily missed. These events are called ‘dropouts’ and considerably hinder analysis of the resulting data. In this work, we propose to make use of gene-gene relationships, learnt from external and more complete datasets, to estimate the true expression of genes that could not be quantified in a given cell. We show that this approach generally outperforms previously published methods, but also that different genes are better estimated with different methods. To allow the community to use our proposed method and combine it with existing ones, we created the R package ADImpute, available through Bioconductor.
Synaptic weight decay with selective consolidation enables fast learning without catastrophic forgetting
Authors: Leimer Pascal , Herzog Michael , Senn Walter
Published: April 2019

Learning can interfere with pre-existing memories that in classical neural networks may lead to catastrophic forgetting. Different from these networks, biological synapses show an early decay of long-term potentiation, combined with a tag & capture mechanism for selective consolidation. We present a 2-component synaptic plasticity model that, by an early decay and a tag & capture mechanism, enables context-dependent fast learning without catastrophic forgetting. For reinforcement learning in multiple contexts, the fast learning combined with an early weight decay maximizes the expected reward while minimizing interferences between subsequent contexts. Fast learning, enabled by a highly plastic weight component, improves performance for a given context. Between contexts this plastic component decays to prevent interference, but selective consolidation into a stable component protects old memories. As a downside of these mechanisms, learning is hampered when consolidation is triggered prematurely by interleaving easy and difficult tasks, consistent with human psychophysical experiments.
Genetic Monitoring and Molecular Phylogeny for Cymothoid Isopod Invasion in Egyptian Lake Qarun Fishes by Using adopted taxonomic marker (COI)
Authors: Hassan Mohammed A.
Published: April 2019

Different types of aquatic ecosystem is abundant by a lot of crustaceans. There are species adapted to maximum of temperature, pressure and salinity. Isopods are a marine parasitic organism and commonly live in warmer seas. They are feeding on blood. Several species settle in the buccal cavity of fish. Parasite became a morbidity case in lake Qarun, GAFRD (General Authority for fish resources development, Fish Statistics yearbook, 2015). DNA barcoding gene (COI gene) was used to make the genetic characterization for the invasive species of Cymothoidae, Cymothoidae sp and recorded in the Genbank. Constructing a phylogeny depending on the degree of similarity between the new record (LC138010.1) and the other records of Cymothoidae species in the Genebank then the environmental conditions were compared according to the analysis of the constructed tree. Suez canal is the primary resource for the fingers of mullet which transferred to Qarun Lake (salinity, 49 ppt). Ballast water have an environmental effect by transferring the alien species in the Suez Gulf which have a warm weather. This study suggests that the Cymothoidae is expanded invasive species came from its habitat regions to a closed lakes which have a similar condition of water environment, temperature and depth to live and to be a morbidity in Lake Quran. Ballast water is a risky way to transfer the invasive species to Suez Canal then New Suez Canal poses and lead to biodiversity risks. Using eDNA techniques to diagnose the invasive species is very important unit which must be established in general authorities of fish resources and development in Egypt and other countries which invaded by different alien species.
Odor Coding of Nestmate Recognition in the Eusocial AntCamponotus floridanus
Authors: Ferguson S.T. , Park K.Y. , Ruff A. , Bakis I. , Zwiebel L.J.
Published: April 2019

Background

In eusocial ants, aggressive behaviors require a sophisticated ability to detect and discriminate between chemical signatures such as cuticular hydrocarbons that distinguish nestmate friends from non-nestmate foes. It has been suggested that a mismatch between a chemical signature (label) and the internal, neuronal representation of the colony odor (template) leads to the recognition of and subsequent aggression between non-nestmates. While several studies have demonstrated that ant chemosensory systems, most notably olfaction, are largely responsible for the decoding of these chemical signatures, a definitive demonstration that odorant receptors are responsible for the detection and processing of the pheromonal signals that regulate nestmate recognition has thus far been lacking. To address this, we have developed an aggression-based bioassay incorporating a suite of highly selective odorant receptor modulators to characterize the role of olfaction in nestmate recognition in the formicine antCamponotus floridanus.

Results

Validation of our aggression-based behavioral assay was carried out by demonstrating an antennal requirement for nestmate recognition. In order to adapt this bioassay for the volatile delivery of Orco modulators, electroantennography was used to show that both a volatilized Orco antagonist (VUANT1) and an Orco agonist (VUAA4) eliminated or otherwise interfered with the electrophysiological responses to the hydrocarbon decane, respectively. Volatilize administration of these compounds to adult workers significantly reduced aggression between non-nestmates without altering aggression levels between nestmates but did not alter aggressive responses towards a mechanical stimulus.

Conclusions

Our studies provide direct evidence that the antennae (as olfactory appendages) and odorant receptors (at the molecular level) are necessary for mediating aggression towards non-nestmates. Furthermore, our observations support a hypothesis in which rejection of non-nestmates depends on the precise detection and decoding of chemical signatures present on non-nestmates as opposed to the absence of any information or the active acceptance of familiar signatures. In addition to describing a novel approach to assess olfactory signaling in genetically intractable insect systems, these studies contribute to a long-standing interest in odor coding and the molecular neuroethology of nestmate recognition.
Phenological matching drives wheat pest range shift under climate change
Authors: Wu Yuqing , Gong Zhongjun , Bebber Daniel P. , Miao Jin , Zhao Zhonghua , Jiang Yuying , Xiao Shihe , Zhang Guoyan , Yu Dazhao , Fang Jichao , Lu Xinmin , Lei Chaoliang , Ding Jianqing , Wang Qiang , Jiang Yueli , Li Tong , Lian Hongmei , Li Huiling , Duan Yun , Huang Jianrong , Jing Donglin , He Yunzhuan , Zhang Zhi , Zhang Yunhui , Chen Julian , Qiao Hongbo , Huang Wenjiang
Published: April 2019

Shifting geographical ranges of crop pests and pathogens in response to climate change pose a threat to food security (1, 2). The orange wheat blossom midge (Sitodiplosis mosellana Géhin) is responsible for significant yield losses in China (3), the world’s largest wheat producer. Here we report that rising temperatures in the North China Plain have resulted in a mean northward range shift of 3.3° (58.8 km per decade) from the 1950s to 2010s, which accelerated to 91.3 km per decade after 1985 when the highly toxic pesticide hexachlorocyclohexane (HCH) was banned (4). Phenological matching between wheat midge adult emergence and wheat heading in this new expanded range has resulted in greater damage to wheat production. Around $286.5 million worth of insecticides were applied to around 19 million hectares in an attempt to minimize wheat midge damage to crops between 1985 and 2016. Despite use of these pesticides, wheat midge caused losses of greater than 0.95 million metric tons of grain during this period. Our results demonstrate the potential for indirect negative impacts of climate change on crop production and food security, and constitute the first large scale example of plant pest range shift due to global warming.
Convolutional Neural Networks for Decoding of Covert Attention Focus and Saliency Maps for EEG Feature Visualization
Authors: Farahat Amr , Reichert Christoph , Sweeney-Reed Catherine M. , Hinrichs Hermann
Published: April 2019

Objective

Convolutional neural networks (CNNs) have proven successful as function approximators and have therefore been used for classification problems including electroencephalography (EEG) signal decoding for brain-computer interfaces (BCI). Artificial neural networks, however, are considered black boxes, because they usually have thousands of parameters, making interpretation of their internal processes challenging. Here we systematically evaluate the use of CNNs for EEG signal decoding and investigate a method for visualizing the CNN model decision process.

Approach

We developed a CNN model to decode the covert focus of attention from EEG event-related potentials during object selection. We compared the CNN and the commonly used linear discriminant analysis (LDA) classifier performance, applied to datasets with different dimensionality, and analyzed transfer learning capacity. Moreover, we validated the impact of single model components by systematically altering the model. Furthermore, we investigated the use of saliency maps as a tool for visualizing the spatial and temporal features driving the model output.

Main results

The CNN model and the LDA classifier achieved comparable accuracy on the lower-dimensional dataset, but CNN exceeded LDA performance significantly on the higher-dimensional dataset (without hypothesis-driven preprocessing), achieving an average decoding accuracy of 90.7% (chance level = 8.3%). Parallel convolutions, tanh or ELU activation functions, and dropout regularization proved valuable for model performance, whereas the sequential convolutions, ReLU activation function, and batch normalization components, reduced accuracy or yielded no significant difference. Saliency maps revealed meaningful features, displaying the typical spatial distribution and latency of the P300 component expected during this task.

Significance

Following systematic evaluation, we provide recommendations for when and how to use CNN models in EEG decoding. Moreover, we propose a new approach for investigating the neural correlates of a cognitive task by training CNN models on raw high-dimensional EEG data and utilizing saliency maps for relevant feature extraction.
PD-L1:CD80 Heterodimer Triggers CD28 While Repressing Both PD-1 and CTLA4 Pathways
Authors: Zhao Yunlong , Lin Chia-Hao , Lee Calvin , Xu Xiaozheng , Huang Zhe , Xiao Changchun , Bui Jack , Lu Li-Fan , Hui Enfu
Published: April 2019

Combined immunotherapy with anti-PD-1/PD-L1 and anti-CTLA4 has resulted in superior clinical responses compared to single agent therapy. The underlying mechanisms for this synergy have yet to be elucidated and investigations have largely focused on cellular interactions. Herein, we report a molecular crosstalk in which the PD-1 ligand PD-L1 and the CTLA4 ligand CD80 heterodimerize incis. This heterodimerization blocks both PD-L1:PD-1 and CD80:CTLA4 interactions, but preserves the ability of CD80 to activate the T cell costimulatory receptor CD28. Remarkably, PD-L1 expression on antigen presenting cells (APCs) protects CD80 from CTLA4 mediatedtrans-endocytosis, and the therapeutic PD-L1 blockade antibody atezolizumab paradoxically downregulates CD80 on APCs, presumably reducing its co-stimulatory ability. Importantly, this effect can be negated by co-blockade of CTLA4 with ipilimumab. Our study reveals an unexpected immune stimulatory role ofcis-acting PD-L1 and a mechanism of anti-PD-L1/anti-CTLA4 crosstalk, providing a therapeutic rationale for combination blockade of PD-L1 and CTLA4.
TLR7-agonist and antineoplastic MEK1/2-inhibitor combination unlocks interferon responses from macrophages
Authors: Yang Lei , Ding Jeak Ling
Published: April 2019

Type I interferons are a family of pleiotropic cytokines that exert anti-tumor actions directly on tumor cells and indirectly on the tumor immune microenvironment (TIME). Hitherto, therapeutic strategies aiming to garner the efficacies of interferon responses are still limited. Here we show a novel strategy that elicits an interferon signature response while targeting both tumor cells using antineoplastic mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) inhibitor and the TIME using toll-like receptor 7 (TLR7)-based immune adjuvant. The combination of MEK1/2 inhibitor and TLR7 agonist unlocked an interferon signature response unexpectedly in macrophages, which was otherwise tightly constrained by TLR7 agonist alone. Deficiency of interferon regulatory factor 1 (Irf1) completely abrogated the responses and prevented the reprogramming of activated macrophages, subduing them in an immunosuppressive state. In a murine melanoma model, combination therapy with TLR7 agonist and MEK1/2 inhibitor synergistically extended survival in wild-type but notIrf1-deficient mice. Specifically, we identified interferon response genes as favorable prognosis markers for cutaneous melanoma patients. Our findings demonstrate a novel strategy for combination therapy that targets both tumor cells and the immunosuppressive TIME through additive effects of monotherapies and synergistic interferon responses.
Kidney osteoclast factors and matrix metalloproteinase expression in a mice model of diet-induced obesity and diabetes
Authors: dos Santos-Macedo Francine , Martins-Gregorio Bianca , Paes-de-Almeida Elan Cardozo , de Souza Mendonça Leonardo , de Souza Azevedo Rebeca , Fernandes-Santos Caroline
Published: April 2019

The role of RANKL/RANK/OPG system on bone remodeling is well known, and there is evidence that it is also important to cardiovascular and kidney pathology, although the underlying mechanisms are not elucidated so far. Thus, we investigated in a mice model of diet-induced obesity and diabetes if renal histopathological changes are associated with the expression of RANKL/RANK/OPG system and matrix metalloproteinases (MMPs). Three months old C57BL/6 mice were fed with control (AIN93M) or high-fat high sucrose (HFHS) diets for 21 weeks (CEUA/UFF #647/15). The HFHS group showed weight gain (+35%, P=0.0001), increased epididymal, inguinal and retroperitoneal fat pad weight (+121 %, P = 0.0006; +287 %, P = 0.0007 and; +286 %, P < 0.0001, respectively), and hyperglycemia (+43%, P=0.02). The kidney of some HFHS fed mice displayed mononuclear inflammatory cell infiltrate (40%), perivascular fibrosis (20%), and focal tubule mineralization (20%). Glomeruli hypertrophy was not detected. Unexpectedly, OPG, RANK, MMP-2 and MMP-9 expression was not altered in HFHS groups (Western blot analysis). In conclusion, the expression of RANKL/RANK/OPG system proteins and MMPs was not influenced by diet-induced obesity and diabetes in the kidney of male C57BL/6 mice, although some adverse histopathological remodeling is noticed in the renal tissue.
Urothelial carcinoma with an NRF1-BRAF rearrangement and response to targeted therapy
Authors: Isaacson Alexandra L. , Guseva Natalya V. , Bossler Aaron D. , Ma Deqin
Published: April 2019

Although BRAF mutations are commonly identified in many solid tumors and the response of BRAF p.V600E-positive tumors to targeted therapy is well documented, BRAF rearrangements are less frequent and are predominantly found in low-grade glioma, melanoma, lung, colorectal, and thyroid carcinoma. Preclinical and clinical studies have demonstrated effectiveness of multiple therapies (RAF-targeted, ERK-targeted, or MEK-targeted) targeting BRAF-fusion harboring tumors. We report a rare NRF1-BRAF fusion with novel breakpoints, identified by next-generation sequencing–based assay, from a 69-year-old man with metastatic urothelial carcinoma (UC) of the renal pelvis and his initial clinical response to a second-generation MEK inhibitor, trametinib, before stopping the medication because of adverse side effects. The NRF1-BRAF fusion has only been reported in a single case of anaplastic pleomorphic xanthoastrocytoma, and BRAF rearrangement has never been reported in UC.
Immune state is associated with natural dietary variation in wild mice Mus musculus domesticus
Authors: Taylor Christopher H. , Young Stuart , Fenn Jonathan , Lamb Angela L. , Lowe Ann E. , Poulin Benoit , MacColl Andrew D. C. , Bradley Janette E.
Published: April 2019

The ability, propensity and need to mount an immune response vary both among individuals and within a single individual over time.

A wide array of parameters has been found to influence immune state in carefully controlled experiments, but we understand much less about which of these parameters are important in determining immune state in wild populations.

Diet can influence immune responses, for example when nutrient availability is limited. We therefore predict that natural dietary variation will play a role in modulating immune state, but this has never been tested.

We measured carbon and nitrogen stable isotope ratios in an island population of house mice Mus musculus domesticus as an indication of dietary variation, and the expression of a range of immune‐related genes to represent immune state.

After accounting for potential confounding influences such as age, sex and helminth load, we found a significant association between carbon isotope ratio and levels of immune activity in the mesenteric lymph nodes, particularly in relation to the inflammatory response.

This association demonstrates the important interplay between diet and an animal's response to immune challenges, and therefore potentially its susceptibility to disease.

A plain language summary is available for this article.
Research note: deblended‐data reconstruction using generalized blending and deblending models
Authors: Ishiyama Tomohide , Ali Mohammed Y. , Ishikawa Satoshi , Blacquiere Gerrit , Nakayama Shotaro
Published: April 2019

We introduce a concept of generalized blending and deblending, develop its models and accordingly establish a method of deblended‐data reconstruction using these models. The generalized models can handle real situations by including random encoding into the generalized operators both in the space and time domain, and both at the source and receiver side. We consider an iterative optimization scheme using a closed‐loop approach with the generalized blending and deblending models, in which the former works for the forward modelling and the latter for the inverse modelling in the closed loop. We applied our method to existing real data acquired in Abu Dhabi. The results show that our method succeeded to fully reconstruct deblended data even from the fully generalized, thus quite complicated blended data. We discuss the complexity of blending properties on the deblending performance. In addition, we discuss the applicability to time‐lapse seismic monitoring as it ensures high repeatability of the surveys. Conclusively, we should acquire blended data and reconstruct deblended data without serious problems but with the benefit of blended acquisition.
Pharmacogenomics guidelines: Current status and future development
Authors: Guo Chengxian , Xie Xiaoxue , Li Jingao , Huang Lihua , Chen Shaojun , Li Xi , Yi Xin , Wu Qin , Yang Guoping , Zhou Honghao , Liu Jun‐Ping , Chen Xiang
Published: April 2019

Genetic polymorphisms impact biological responses to drugs. Current pharmacogenomics guidelines formulated by different countries, such as the Clinical Pharmacogenetics Implementation Consortium, the Dutch Pharmacogenetics Working Group, the Canadian Pharmacogenomics Network for Drug Safety, and the French National Network (Réseau) of Pharmacogenetics, play important roles in clinical practices. However, the standards for these guidelines vary significantly, resulting in differences in recommendations. The present article discusses these differences by head‐to‐head comparison of the existing pharmacogenomics guidelines and proposes new strategies for their future development.
Greening Nigeria's economy for industrial and environmental sustainability: Polyurethane production as a test case
Authors: Momodu Abiodun S. , Aransiola Elizabeth F. , Okunade Inioluwa D. , Ogunlusi Grace O. , Awokoya Kehinde N. , Ogundari Ibikunle O. , Falope Olutope T. , Makinde Oladotun W. , Akinbami John‐Felix K.
Published: April 2019

The study focused on Nigeria's polyurethane (PU) production process as a test case. Though it is currently insignificant when viewed from a global perspective, PU production in Nigeria is not eco‐friendly. Traditionally, PU is produced by reacting petro‐based polyol with a poly‐isocyanate, which is made from amines and phosgene and are currently imported into the country. These two materials are detrimental to the human health and environment, indicating that Nigeria's PU industries need to re‐examine their production inputs for environmental compliance. The objective of this study is to review the PU industry for nontoxic reagents that could be sourced locally vis‐à‐vis overcoming sustainable development (greening the economy) challenges in Nigeria. Non‐isocyanate polyurethane (NIPU) is preferred to petro‐polyurethane because, in comparison, NIPU has improved thermal and chemical resistance, porosity and water absorption, and is less toxic. Engaging local resources to produce PU is economically feasible; in addition, NIPU is relatively advantageous to human health and the environment. Aside from being economically feasible, production of NIPU in Nigeria has the propensity to greatly enlarge the growth of the existing PU industry to tremendous heights and contribute to diversifying and improving the overall economy.
The Common Agricultural Policy's New Delivery Model Post‐2020: National Administration Perspective
Authors: Carey Mary
Published: April 2019

This article assesses the June 2018 European Commission's legislative proposals for the Common Agricultural Policy (CAP) post‐2020. It does not consider the positions of the co‐legislators – the Council of Ministers and the European Parliament. The article considers the European Commission's New Delivery Model (NDM), the enhanced environmental and climate ambition, and the new performance framework from the perspective of a national administration. The enhanced focus on performance is the cornerstone of the NDM. However, the article highlights the complexity associated with enhanced reporting requirements of the NDM and asserts that the reporting requirements will need to be simplified and streamlined to ensure a simplified CAP for all involved; and to encourage the enhanced environmental and climate ambition foreseen in the European Commission's proposal. The move from compliance‐based to performance‐based oversight is welcomed from the perspective of the national administration. The single audit approach, whereby multiple audits and inspections are avoided, should result in simplification for the CAP beneficiaries and for the national administrations. The proposed NDM is very different to what the European Commission, national administrations and beneficiaries are used to – it will take time to bed down.
The Future of US Farm Policy
Authors: Smith Vincent H. , Glauber Joseph W.
Published: April 2019

The farm bill is the primary legislative vehicle for federal food and agricultural policies in the United States that is renewed roughly once every five years. Most current farm bill subsidy and other domestic support programmes for agriculture have their origins in legislation introduced in the 1930s to alleviate poverty among farm households during the Great Depression. Although US farm households have enjoyed higher incomes and wealth than the average US family for many years, legislation to support agricultural commodity prices and to increase farm incomes has persisted. A new farm bill offers the US Congress an opportunity to reform agricultural subsidy policies. But if recent history is a guide, what will emerge is likely to resemble much of what was in the 2014 bill. As was the case with that bill, maintaining the status quo will represent a missed opportunity to cut farm subsidies and make agricultural programmes more market oriented, and be unlikely to improve trade relations for the United States in the context of its commitments under current World Trade Organization agreements. In many ways, agricultural policy in the United States seems to be firmly marching back to the past rather than looking to the future.
Generation of a highly attenuated strain of Pseudomonas aeruginosa for commercial production of alginate
Authors: Valentine Meagan E. , Kirby Brandon D. , Withers Thomas R. , Johnson Shannon L. , Long Timothy E. , Hao Youai , Lam Joseph S. , Niles Richard M. , Yu Hongwei D.
Published: April 2019

Alginate is an important polysaccharide that is commonly used as a gelling agent in foods, cosmetics and healthcare products. Currently, all alginate used commercially is extracted from brown seaweed. However, with environmental changes such as increasing ocean temperature and the increasing number of biotechnological uses of alginates with specific properties, there is an emerging need for more reliable and customizable sources of alginate. An alternative to seaweed for alginate production is Pseudomonas aeruginosa, a common Gram‐negative bacterium that can form alginate‐containing biofilms. However, P. aeruginosa is an opportunistic pathogen that can cause life‐threatening infections in immunocompromised patients. Therefore, we sought to engineer a non‐pathogenic P. aeruginosa strain that is safe for commercial production of alginate. Using a homologous recombination strategy, we sequentially deleted five key pathogenicity genes from the P. aeruginosa chromosome, resulting in the marker‐free strain PGN5. Intraperitoneal injection of mice with PGN5 resulted in 0% mortality, while injection with wild‐type P. aeruginosa resulted in 95% mortality, providing evidence that the systemic virulence of PGN5 is highly attenuated. Importantly, PGN5 produces large amounts of alginate in response to overexpression of MucE, an activator of alginate biosynthesis. The alginate produced by PGN5 is structurally identical to alginate produced by wild‐type P. aeruginosa, indicating that the alginate biosynthetic pathway remains functional in this modified strain. The genetic versatility of P. aeruginosa will allow us to further engineer PGN5 to produce alginates with specific chemical compositions and physical properties to meet different industrial and biomedical needs.
Hydroclimatology of the Mississippi River Basin
Authors: McCabe Gregory J. , Wolock David M.
Published: April 2019

Model estimated monthly water balance (WB) components (i.e., potential evapotranspiration, actual evapotranspiration, and runoff [R]) for 848 United States (U.S.) Geological Survey 8‐digit hydrologic units located in the Mississippi River Basin (MRB) are used to examine the temporal and spatial variability of the MRB WB for water years 1901 through 2014. Results indicate the MRB can be divided into nine subregions with similar temporal variability in R. The WB analyses indicated ~79% of total water‐year MRB runoff is generated by four of the nine subregions and most of the R in the basin is derived from surplus (S) water during the months of December through May. Furthermore, the analyses showed temporal variability in S is largely controlled by the occurrence of negative atmospheric pressure anomalies over the western U.S. and positive atmospheric pressure anomalies over the eastern U.S. coast. This combination of atmospheric pressure anomalies results in an anomalous flow of moist air from the Gulf of Mexico into the MRB. In the context of paleo‐climate reconstructions of the Palmer Drought Severity Index, since about 1900 the MRB has experienced wetter conditions than were experienced during the previous 500 years.