bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of PD-L1 and PD-1 Expression and CD8+ Tumor-infiltrating Lymphocyte in Epstein-Barr Virus-associated Nasopharyngeal Carcinoma
Authors: Larbcharoensub Noppadol , Mahaprom Komkrit , Jiarpinitnun Chuleeporn , Trachu Narumol , Tubthong Nattha , Pattaranutaporn Poompis , Sirachainan Ekaphop , Ngamphaiboon Nuttapong 
Published: April 2018

Objectives:
Immunotherapies that target the programmed death-1/ programmed death-1 ligand (PD-1/PD-L1) immune checkpoint pathway have shown promise in nasopharyngeal carcinoma (NPC) in early phases clinical studies. Here, we evaluated PD-1 and PD-L1 expression and CD8+ tumor-infiltrating lymphocytes (TILs) in NPC patients.

Materials and Methods:
Newly diagnosed NPC patients were identified through the institutional database between January 2007 and December 2012. PD-L1 and PD-1 expression, Epstein-Barr virus (EBV) status, and CD8+ TIL numbers were measured in archival tumor samples at diagnosis and their correlations with clinicopathologic features, including survival, were evaluated.

Results:
A total of 114 NPC patients were analyzed. Most patients (96%) were EBV positive. PD-L1 was expressed in ≥1% of tumor cells (TCs) in 69% of patients, in ≥50% of TCs in 12% of patients, and in ≥5% of either TCs or infiltrating immune cells in 71% of patients. CD8+ TILs were present in tumors from all patients, whereas only 11% of tumors expressed PD-1. There were no correlations between PD-L1 expression and CD8+ TIL abundance, PD-1 expression, or survival.

Conclusions:
Approximately 70% of EBV-positive NPC expressed PD-L1, but this did not correlate with patient survival or clinicopathologic features. The findings of this study represent the immune biomarker profile of confirmed EBV-associated NPC in an endemic region. Since the current clinical development of immune checkpoint inhibitor for NPC is mostly focusing on an EBV-associated tumor, differences in immune biomarker profiles and EBV status of endemic and nonendemic regions should be further explored.
Downregulation of adenosine and adenosine A1 receptor contributes to neuropathic pain in resiniferatoxin neuropathy
Authors: Kan Hung-Wei , Chang Chin-Hong , Lin Chih-Lung , Lee Yi-Chen , Hsieh Sung-Tsang , Hsieh Yu-Lin 
Published: April 2018

Abstract
The neurochemical effects of adenosine signaling in small-fiber neuropathy leading to neuropathic pain are yet to be explored in a direct manner. This study examined this system at the level of ligand (through the ectonucleotidase activity of prostatic acid phosphatase [PAP]) and adenosine A1 receptors (A1Rs) in resiniferatoxin (RTX) neuropathy, a peripheral neurodegenerative disorder that specifically affects nociceptive nerves expressing transient receptor potential vanilloid type 1 (TRPV1). We conducted immunohistochemistry on dorsal root ganglion (DRG) neurons, high-performance liquid chromatography for functional assays, and pharmacological interventions to alter PAP and A1Rs in mice with RTX neuropathy. In DRG of RTX neuropathy, PAP(+) neurons were reduced compared with vehicle-treated mice (P = 0.002). Functionally, PAP ectonucleotidase activity was consequently reduced (ie, the content of adenosine in DRG, P = 0.012). PAP(+) neuronal density was correlated with the degree of mechanical allodynia, which was reversed by intrathecal (i.t.) lumbar puncture injection of recombinant PAP with a dose-dependent effect. Furthermore, A1Rs were downregulated (P = 0.002), and this downregulation was colocalized with the TRPV1 receptor (31.0% ± 2.8%). Mechanical allodynia was attenuated in a dose-dependent response by i.t. injection of the A1R ligand, adenosine; however, no analgesia was evident when an exogenous adenosine was blocked by A1R antagonist. This study demonstrated dual mechanisms of neuropathic pain in TRPV1-induced neuropathy, involving a reduced adenosine system at both the ligand (adenosine) and receptor (A1Rs) levels.
Cajal Cell Counts are Important Predictors of Outcomes in Drug Refractory Gastroparesis Patients With Neurostimulation
Authors: Omer Endashaw , Kedar Archana , Nagarajarao Harsha S. , Nikitina Yana , Vedanarayanan Vetta , Subramony Charu , Lahr Christopher J. , Abell Thomas L. 
Published: April 2018

Background and Aims:
Cajal cells serve as the pacemaker cells of the gastrointestinal tract and regulates peristalsis. On the baisis of that fact, it has been hypothesized that a decrease in Cajal cells can lead to gastroparesis and other motility issues. Treatment with medications has a limited efficacy and most resort to gastric electrical stimulation (GES) devices for symptomatic relief. We believe that the number of Cajal cells present is directly proportional to symptomatic relief with GES.

Materials and Methods:
Twenty-three (white female) subjects were recruited from the gastric motility clinic University of Mississipi for this study with the criteria of drug refractory gastropersis. Symptoms were measured using Likert scale and gastric emptying times were measured pre-GES and post-GES. Serosal electrogram measurements were recorded during surgical placement of permanent electrical stimulator under various modes. Cajal cell count scoring via immunohistochemistry were performed during the implantaion of the GES.

Results:
The data were grouped in 2 categories based on the Cajal cells that is ≥2.00 and <2.00. Subjects with higher Cajal cells reported a statiscially improvement in gastroperesis symptoms. Significant differences were also noted in the first hour gastric emptying study. The mean group difference is 17.5 (95% confidence interval, 1.41-33.58; P=0.035). Serosal amplitude differences were noted being significantly higher in the group with ≥2 cajal cells.

Conclusions:
Electrograms obtained after GES demonstrates immediate improvement in gastric electrical activity and gastroparesis symptoms in patients with relatively higher Cajal cell counts when compared with patients with extensive loss of Cajal cells.
Developments in the Transition From Animal Use to Simulation-Based Biomedical Education
Authors: Pawlowski John B. , Feinstein David M. , Gala Shalin G. 
Published: April 2018

Summary Statement
There has been a significant shift from the use of animals in biomedical training exercises toward simulation-based education methods. The transition has been driven by technological advances, empirical evidence of improved student outcomes, cost-effectiveness, and a growing concern for the welfare of animals. These factors have spurred policy changes worldwide in how medical and science curricula are delivered. We detail how some of these policy changes evolved and comment on the future direction of simulation-based education and its implications for healthcare providers, instructors, and the general public.
Surgical Telementoring Without Encumbrance
Authors: Rojas-Muñoz Edgar , Cabrera Maria Eugenia , Andersen Daniel , Popescu Voicu , Marley Sherri , Mullis Brian , Zarzaur Ben , Wachs Juan 
Published: April 2018

Objective:
This study investigates the benefits of a surgical telementoring system based on an augmented reality head-mounted display (ARHMD) that overlays surgical instructions directly onto the surgeon's view of the operating field, without workspace obstruction.

Summary Background Data:
In conventional telestrator-based telementoring, the surgeon views annotations of the surgical field by shifting focus to a nearby monitor, which substantially increases cognitive load. As an alternative, tablets have been used between the surgeon and the patient to display instructions; however, tablets impose additional obstructions of surgeon's motions.

Methods:
Twenty medical students performed anatomical marking (Task1) and abdominal incision (Task2) on a patient simulator, in 1 of 2 telementoring conditions: ARHMD and telestrator. The dependent variables were placement error, number of focus shifts, and completion time. Furthermore, workspace efficiency was quantified as the number and duration of potential surgeon-tablet collisions avoided by the ARHMD.

Results:
The ARHMD condition yielded smaller placement errors (Task1: 45%, P < 0.001; Task2: 14%, P = 0.01), fewer focus shifts (Task1: 93%, P < 0.001; Task2: 88%, P = 0.0039), and longer completion times (Task1: 31%, P < 0.001; Task2: 24%, P = 0.013). Furthermore, the ARHMD avoided potential tablet collisions (4.8 for 3.2 seconds in Task1; 3.8 for 1.3 seconds in Task2).

Conclusion:
The ARHMD system promises to improve accuracy and to eliminate focus shifts in surgical telementoring. Because ARHMD participants were able to refine their execution of instructions, task completion time increased. Unlike a tablet system, the ARHMD does not require modifying natural motions to avoid collisions.
Association of Preoperative Anticholinergic Medication Exposure With Postoperative Healthcare Resource Use and Outcomes
Authors: McIsaac Daniel I. , Wong Coralie A. , Diep Deric , van Walraven Carl 
Published: April 2018

Objective:
The aim of this study was to measure the association of preoperative anticholinergic exposure with length of stay (LOS) and other outcomes in older people having elective noncardiac surgery.

Summary Background Data:
Anticholinergic medications are associated with adverse events in nonsurgical populations; the association of anticholinergic medications with outcomes in elective surgery patients is poorly described.

Methods:
We conducted a retrospective, population-based cohort study using linked administrative data in Ontario, Canada. We identified all people >65 years old, from 2003 to 2014, having major, elective noncardiac surgery. Anticholinergic medication exposure was quantified using the Anticholinergic Risk Scale (ARS). Multilevel, multivariable modeling measured the adjusted association of ARS with LOS (primary outcome), institutional discharge, readmissions, costs, and survival (secondary outcomes).

Results:
Of 245,410 individuals, 71,569 had anticholinergic exposure (ARS 1–2, 15.6%; ARS ≥3, 13.6%). Median LOS was 5 days (interquartile range 3–7). Using proportional hazards analysis to model time to discharge, adjusting for in-hospital death as a competing risk, and surgical risk, demographic characteristics, and comorbidities, higher ARS scores were associated with longer LOS [smaller hazard ratios (HRs) mean longer LOS; ARS 1–2: adjusted HR 0.94, 95% confidence interval (CI), 0.93–0.95, P < 0.0001; ARS ≥3: adjusted HR 0.93, 95% CI, 0.91–0.95, P < 0.0001]. Similar associations were observed for all secondary outcomes.

Conclusions:
Increasing ARS scores were associated with increased LOS, decreased survival, higher rates of institutional discharge and readmission, and higher costs of care. Perioperative interventional research to reduce the anticholinergic exposure in older surgical patients is likely warranted.
Derivation and Validation of a Generalizable Preoperative Frailty Index Using Population-based Health Administrative Data
Authors: McIsaac Daniel I. , Wong Coralie A. , Huang Allen , Moloo Husein , van Walraven Carl 
Published: April 2018

Objective:
To develop and validate a preoperative frailty index (pFI) for use in population-based health administrative (HA) data.

Summary Background Data:
Frailty is a robust predictor of adverse postoperative outcomes. Population-level frailty measures used in surgical studies have significant methodological limitations. Frailty indices (FIs) are a well-defined approach to measuring frailty with well-described methods for development and evaluation. An appropriate preoperative FI in HA data has not been derived or evaluated.

Methods:
Retrospective cohort study using linked HA data in Canada. We identified people >65 years (2002–2015) who had major elective or emergency surgery. Standardized methods were used to construct a 30-variable pFI. Unadjusted and multilevel, multivariable adjusted models were used to measure the association of the pFI with 1-year mortality and institutional discharge. Elective patients were the derivation cohort, emergency patients were the validation cohort. Prespecified sensitivity analyses were performed.

Results:
We identified 415,704 elective, and 95,581 emergency patients. The elective 1-year mortality rate was 4.7%. Thirty percent of population-level deaths occurred in people with frailty. Every 0.1-unit increase in the pFI was associated with a 2.20-fold increase in the adjusted odds of mortality (95% CI 2.15–2.26; c-statistic 0.81), and a 1.70-fold increase in institutional discharge (95% CI 1.59–1.80; c-statistic 0.71). pFI performance was similar in emergency patients, and was robust to changes in index composition.

Conclusions:
A preoperative FI derived from HA data is a robust method to measure frailty in elective and emergency patients. Generalizable FIs should be considered a standard approach to population-level study of surgical frailty.
Effects of Different Levels of Intra-Abdominal Pressure on the Postoperative Hepatic Function of Patients Undergoing Laparoscopic Cholecystectomy: A Systematic Review and Meta-Analysis
Authors: Cheng Zheng-Jun , Wang Yun-Bing , Chen Long , Gong Jian-Ping , Zhang Wei 
Published: April 2018

Objective:
The aim of this meta-analysis is to compare the differences in postoperative markers of the hepatic function under different intra-abdominal pressures in laparoscopic cholecystectomy (LC).

Methods:
Several databases were searched for control studies, and then the weighted data were pooled with random-effect models.

Results:
A total of 11 studies involving 865 patients were included. The meta-analysis reveals that the level of the aspartate aminotransferase and alanine transaminase of the low-pressure group has a lower postoperative increase than the moderate-pressure group (P<0.001). The level of the aspartate aminotransferase and alanine transaminase of the moderate-pressure group has a lower postoperative increase than the high-pressure group (P<0.001). Totally, the effect of lower pressure LC on postoperative hepatic functions is less significant than that of the higher one. Potential subgroup analysis does not modify these results.

Conclusions:
The recommended pressure in LC is suggested to be lower so as to result in a better surgical safety, especially for special populations.
Integrated deep visual and semantic attractor neural networks predict fMRI pattern-information along the ventral object processing pathway
Authors: Devereux Barry J. , Clarke Alex , Tyler Lorraine K. 
Published: April 2018

ABSTRACTRecognising an object involves rapid visual processing and activation of semantic knowledge about the object, but how visual processing activates and interacts with semantic representations remains unclear. Cognitive neuroscience research has shown that while visual processing involves posterior regions along the ventral stream, object meaning involves more anterior regions, especially perirhinal cortex. Here we investigate visuo-semantic processing by combining a deep neural network model of vision with an attractor network model of semantics, such that visual information maps onto object meanings represented as activation patterns across features. In the combined model, concept activation is driven by visual input and co-occurrence of semantic features, consistent with neurocognitive accounts. We tested the model’s ability to explain fMRI data where participants named objects. Visual layers explained activation patterns in early visual cortex, whereas pattern-information in perirhinal cortex was best explained by later stages of the attractor network, when detailed semantic representations are activated. Posterior ventral temporal cortex was best explained by intermediate stages corresponding to initial semantic processing, when visual information has the greatest influence on the emerging semantic representation. These results provide proof of principle of how a mechanistic model of combined visuo-semantic processing can account for pattern-information in the ventral stream.
Burst firing and spatial coding in subicular principal cells
Authors: Simonnet Jean , Brecht Michael 
Published: April 2018

AbstractThe subiculum is the major output structure of the hippocampal formation and is involved in learning and memory as well as in spatial navigation. Little is known about how the cellular diversity of subicular neurons is related to function. Primed by in vitro studies, which identified distinct bursting patterns in subicular cells, we asked how subicular burst firing is related to spatial coding in vivo. Using high-resolution juxtacellular recordings in freely moving rats, we analyzed the firing patterns of 51 subicular principal neurons and distinguished two populations based on their bursting behavior, i.e. sparsely bursting (∼80%) and dominantly bursting neurons (∼20%). Dominantly bursting neurons had significantly higher firing rates than sparsely bursting neurons. Furthermore, the two clusters had distinct spatial properties, sparsely bursting cells showing strong positional tuning and dominantly bursting cells being only weakly tuned. Additionally, the occurrence of bursts in sparsely bursting neurons defined well-defined spatial fields. In contrast, isolated spikes contained less spatial information. We conclude that burst firing distinguishes subicular principal cell types and constitutes a distinct unit encoding spatial information in sparsely bursting spatial cells. Overall, our results demonstrate that burst firing is highly relevant to subicular space coding.
Dynamic and causal contribution of parietal circuits to perceptual decisions during category learning
Authors: Zhong Lin , Zhang Yuan , Duan Chunyu A. , Pan Jingwei , Xu Ning-long 
Published: April 2018

AbstractMaking perceptual decisions to categorize unknown sensory stimuli is a fundamental cognitive function, known as category learning. The posterior parietal cortex (PPC), although has been intensively studied for its role in decision-making and other cognitive functions, its causal link with behavior remains controversial. Here we combine in vivo two-photon imaging, circuit manipulation and auditory psychophysics behavior in mice to probe the role of PPC and its connectivity with sensory cortex in decision-making during category learning. We show that PPC neuronal populations exhibit coding dynamics characteristic of category learning, showing representations for both new sensory stimuli and prior learned categories. Circuit-specific perturbations of PPC and its projections to auditory cortex impaired decision performance specifically for categorizing new auditory stimuli. These data reveal a dynamic and causal role of the parietal-auditory circuit in decision-making, integrating prior knowledge to guide categorical decisions on new sensory stimuli.
Using genetic drug-target networks to develop new drug hypotheses for major depressive disorder
Authors: Gaspar Héléna A , Gerring Zachary , Hübel Christopher , Middeldorp Christel M , Derks Eske M , Breen Gerome 
Published: April 2018

AbstractThe major depressive disorder (MDD) working group of the Psychiatric Genomics Consortium (PGC) has published a genome-wide association study (GWAS) for MDD in 130,664 cases, identifying 44 risk variants. We used these results to investigate potential drug targets and repurposing opportunities. We built easily interpretable bipartite drug-target networks integrating interactions between drugs and their targets, genome-wide association statistics and genetically predicted expression levels in different tissues, using our online tool Drug Targetor (drugtargetor.com). We also investigated drug-target relationships and drug effects on gene expression that could be impacting MDD. MAGMA was used to perform pathway analyses and S-PrediXcan to investigate the directionality of tissue-specific expression levels in patients vs. controls. Outside the major histocompatibility complex (MHC) region, 25 druggable genes were significantly associated with MDD after multiple testing correction, and 19 were suggestively significant. Several drug classes were significantly enriched, including monoamine reuptake inhibitors, sex hormones, antipsychotics and antihistamines, indicating an effect on MDD and potential repurposing opportunities. These findings require validation in model systems and clinical examination, but also show that GWAS may become a rich source of new therapeutic hypotheses for MDD and other psychiatric disorders that need new – and better – treatment options.
Structural analysis of the active site and DNA binding of human cytidine deaminase APOBEC3B
Authors: Hou Shurong , Slivas Tania V. , Leidner Florian , Nalivaika Ellen A. , Matsuo Hiroshi , Yilmaz Nese Kurt , Schiffer Celia A. 
Published: April 2018

AbstractAPOBEC3s proteins (A3s), a family of human cytidine deaminases, protect the host cell from endogenous retro-elements and exogenous viral infections by introducing hypermutations. However, the ability to mutate genomic DNA makes A3s a potential cancer source. Of the 7 human A3s, A3B has been implicated as an endogenous cause for multiple cancers. Despite overall similarity, A3s have distinct deamination activity with A3B among the least catalytically active. Over the past few years, several structures of apo as well as DNA-bound A3 proteins have been determined. These structures revealed the molecular determinants of nucleotide specificity and the importance of the loops around the active site in DNA binding. However, for A3B, the structural basis for regulation of deamination activity and the role of active site loops in coordinating DNA had remained unknown. In this study, using a combination of advanced molecular modelling followed by experimental mutational analysis and dynamics simulations, we investigated molecular mechanism of A3B regulating activity and DNA binding. We identified a unique auto-inhibited conformation of A3B that restricts access and binding of DNA to the active site, mainly due to the extra PLV residues in loop 1. We modelled DNA binding to fully native A3B and found that Arg211 in the arginine patch of loop1 is the gatekeeper while Arg212 stabilizes the bound DNA. This model also identified the critical residues for substrate specificity, especially at the -1 position. Our results reveal the structural basis for relatively lower catalytic activity of A3B and provide opportunities for rational design of inhibitors that specifically target A3B to benefit cancer therapeutics.
Governance implications of the UN higher education sustainability initiative
Authors: Moon Christopher J. , Walmsley Andreas , Apostolopoulos Nikolaos 
Published: April 2018

Purpose
This paper aims to review the progress of a sample of (n = 307) signatories in the Higher Education Sustainability Initiative which commits higher education institutions (HEIs) to make smart commitments to achieve one or more of the UN sustainable development goals (SDGs).

Design/methodology/approach
A preliminary survey of n = 307 HEIs via online questionnaire and database search was conducted.

Findings
Findings reveal a difference between HEI governance, that is “instrumental”, and governance, that is “holistic”, in relation to sustainability.

Research limitations/implications
Implications identified for achieving SDGs in general and for academic–business partnerships, in particular.

Practical implications
Practical implications for enterprise (developing a tool to measure sustainability mindset) and for enterprise education (sharing of best practices from other HEIs).

Social implications
Improved understanding of the sustainability mindset will inform decisions about approaches to governing and operationalising sustainability in organisations.

Originality/value
The survey is not original but the emphasis on sustainability mindset (compassion, empathy and connectedness to SDGs) is.