bluuebunny/crossref_metadata_2025_split huggingface dataset:
Late-Stage Tumor Regression after PD-L1 Blockade Plus a Concurrent OX40 Agonist
Authors: Polesso Fanny , Weinberg Andrew D. , Moran Amy E. 
Published: December 2018

Abstract
The protective capability of tumor antigen–specific T cells is regulated by costimulatory and inhibitory signals. Current approaches in cancer immunotherapy seek to restore the function of unresponsive T cells by blocking inhibitory pathways. In contrast, providing exogenous costimulatory signals to T cells also enhances antitumor functionality. By combining these two clinical approaches, we demonstrate the synergy of targeting PD-L1 together with the costimulatory molecule OX40, to enhance antitumor immunity. Concurrently blocking PD-L1 and providing a costimulatory agonist to OX40 increased the presence and functionality of tumor antigen–specific CD8+ T cells with simultaneous enhancement of T-helper type 1 (Th1)-skewed CD4+ T cells. This shift was functionally supported by increased glucose metabolism of antigen-specific CD8+ T cells and the acquisition of granzyme B by regulatory T cells. Together, this mechanism promoted tumor regression of late-stage tumors beyond that achieved by either blockade as monotherapy. These findings indicate that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen–specific T cells.
Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis
Authors: Harmon Cathal , Robinson Mark W. , Hand Fiona , Almuaili Dalal , Mentor Keno , Houlihan Diarmaid D. , Hoti Emir , Lynch Lydia , Geoghegan Justin , O'Farrelly Cliona 
Published: December 2018

Abstract
Colorectal cancer is the third most common malignancy worldwide, with 1.3 million new cases annually. Metastasis to the liver is a leading cause of mortality in these patients. In human liver, metastatic cancer cells must evade populations of liver-resident natural killer (NK) cells with potent cytotoxic capabilities. Here, we investigated how these tumors evade liver NK-cell surveillance. Tissue biopsies were obtained from patients undergoing resection of colorectal liver metastasis (CRLM, n = 18), from the tumor, adjacent tissue, and distal resection margin. The number and phenotype of liver-resident NK cells, at each site, were analyzed by flow cytometry. Tumor-conditioned media (TCM) was generated for cytokine and metabolite quantification and used to treat healthy liver-resident NK cells, isolated from donor liver perfusate during transplantation. Liver-resident NK cells were significantly depleted from CRLM tumors. Healthy liver-resident NK cells exposed to TCM underwent apoptosis in vitro, associated with elevated lactate. Tumor-infiltrating liver-resident NK cells showed signs of mitochondrial stress, which was recapitulated in vitro by treating liver-resident NK cells with lactic acid. Lactic acid induced apoptosis by decreasing the intracellular pH of NK cells, resulting in mitochondrial dysfunction that could be prevented by blocking mitochondrial ROS accumulation. CRLM tumors produced lactate, thus decreasing the pH of the tumor microenvironment. Liver-resident NK cells migrating toward the tumor were unable to regulate intracellular pH resulting in mitochondrial stress and apoptosis. Targeting CRLM metabolism provides a promising therapeutic approach to restoring local NK-cell activity and preventing tumor growth.
Preliminary Experience Using Motion Compensated CINE Magnetic Resonance Imaging to Visualise Fetal Congenital Heart Disease
Authors: Roy Christopher W. , Marini Davide , Lloyd David F. A. , Mawad Wadi , Yoo Shi-Joon , Schrauben Eric M. , Jaeggi Edgar , Seed Mike , Macgowan Christopher K. 
Published: December 2018

Background:
Recent advances in cardiovascular magnetic resonance (CMR) imaging have facilitated CINE imaging of the fetal heart. In this work, a preliminary investigation of the utility of multislice CINE CMR for assessing fetal congenital heart disease is performed and compared with echocardiography.

Methods and Results:

Multislice CINE CMR and echocardiography images were acquired in 25 pregnant women wherein the fetus had a suspected congenital heart defect based on routine obstetric ultrasound. Pathognomonic images were identified for each subject for qualitative comparison of CMR and echocardiography. Quantitative comparison of CMR and echocardiography was then performed by 2 reviewers using a binary scoring of 9 fetal cardiac anatomic features (identifiable/not-identifiable). Pathognomonic images demonstrated the ability of CMR to visualize a variety of congenital heart defects. Overall CMR was able to identify the majority of the 9 assessed fetal cardiac anatomic features (reviewer 1, 7.1±2.1; reviewer 2, 6.7±2.3). Although both reviewers identified more anatomic features with echocardiography (reviewer 1, 7.8±2.3; reviewer 2, 7.5±2.4;
P
=0.01), combining information from both modalities enabled identification of additional anatomic features across subjects (reviewer 1, 8.4±1.3; reviewer 2, 8.4±1.2). The primary limiting factor for CMR was inadequate coverage of the fetal cardiac anatomy or noncontiguous slices because of gross fetal movement.

Conclusions:
CINE CMR enables visualization of fetal congenital heart disease. This work demonstrates the potential of CMR for diagnosing congenital heart disease in utero in conjunction with echocardiography during late gestation.
Days Alive and Out of Hospital: Exploring a Patient-Centered, Pragmatic Outcome in a Clinical Trial of Patients With Acute Coronary Syndromes
Authors: Fanaroff Alexander C. , Cyr Derek , Neely Megan L. , Bakal Jeffery , White Harvey D. , Fox Keith A.A. , Armstrong Paul W. , Lopes Renato D. , Ohman E. Magnus , Roe Matthew T. 
Published: December 2018

Background
Cardiovascular clinical trials have traditionally incorporated separate time-to-first-event analyses for their primary efficacy and safety comparisons, but this framework has a number of limitations, including limited patient-centeredness and a traditional requirement for central adjudication. Days alive and out of the hospital (DAOH) has the potential to provide additional insight.

Methods and Results
TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) was a randomized, multinational clinical trial that compared the effect of prasugrel versus clopidogrel in patients stabilized after non-ST segment elevation acute coronary syndrome treated without revascularization; the trial had a neutral result. DAOH was calculated for each patient using site-submitted adverse event reporting data. We described patterns of DAOH overall, and among younger adults (<75 years old), older adults (≥75 years old), and frail/prefrail patients over 12 months follow-up and used Poisson regression to compare DAOH for patients randomized to prasugrel versus clopidogrel. Of 9249 patients in the overall trial population, 500 (5.4%) died, and 2504 (27.1%) were hospitalized 4150 times over 12 months’ follow-up; the mean±SD DAOH was 317±86. The distribution of DAOH over 12 months was left-skewed, with median DAOH 363 days. Among younger adults, older adults, and frail/prefrail patients, mean DAOH were 323, 293, and 304 days, respectively. There were no differences in DAOH by treatment arm in the overall population (rate ratio, 1.00; 95% CI, 0.99–1.01) or any subgroup.

Conclusions
These results support the feasibility of determining DAOH, a patient-centered outcome that can potentially overcome many of the disadvantages of the traditional time-to-composite-event framework in the clinical trial setting.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov.
Unique identifier: NCT00699998.
C-band Dual-Polarization Radar Signatures of Wet Downbursts around Cape Canaveral, Florida
Authors: Amiot Corey G. , Carey Lawrence D. , Roeder William P. , McNamara Todd M. , Blakeslee Richard J. 
Published: December 2018

Abstract
Wind warnings are the second-most-frequent advisory issued by the U.S. Air Force’s 45th Weather Squadron (45WS) at Cape Canaveral, Florida. Given the challenges associated with nowcasting convection in Florida during the warm season, improvements in 45WS warnings for convective wind events are desired. This study aims to explore the physical bases of dual-polarization radar signatures within wet downbursts around Cape Canaveral and identify signatures that may assist the 45WS during real-time convective wind nowcasting. Data from the 45WS’s C-band dual-polarization radar were subjectively analyzed within an environmental context, with quantitative wind measurements recorded by weather tower sensors for 32 threshold-level downbursts with near-surface winds ≥ 35 kt (1 kt ≈ 0.51 m s−1) and 32 null downbursts. Five radar signatures were identified in threshold-level downburst-producing storms: peak height of 1-dB differential reflectivity ZDR column, peak height of precipitation ice signature, peak reflectivity, height below 0°C level where ZDR increases to 3 dB within a descending reflectivity core (DRC), and vertical ZDR gradient within DRC. Examining these signatures directly in updraft–downdraft cycles that produced threshold-level winds yielded mean lead times of 20.0–28.2 min for cumulus and mature stage signatures and 12.8–14.9 min for dissipating stage signatures, with higher signature test values generally yielding higher skill scores. A conceptual test of utilizing signatures within earlier cells in multicell storms to indirectly predict the potential for intense downbursts in later cells was performed, which offered increased lead times and skill scores for an Eulerian forecast region downstream from the storm initiation location.
Safety and Effectiveness of Intravenous Chlorpromazine for Agitation in Critically Ill Patients
Authors: Choi Mia , Barra Megan E. , Newman Kelly , Sin Jonathan H. 
Published: December 2018

Background: Agitation is common in the intensive care unit (ICU). Although antipsychotics are frequently used as first-line therapy, chlorpromazine has fallen out of favor due to risk of cardiovascular complications and severe hypotension. Although chlorpromazine is used anecdotally, there is a lack of data regarding its safety and effectiveness. The objective of this study was to investigate the use of intravenous (IV) chlorpromazine for agitation in the ICU setting. Methods: A retrospective review was performed at a tertiary care academic medical center. Patients were included if they received IV chlorpromazine in the ICU for agitation, infused at a rate of 1 mg/min. Primary end points were change in systolic blood pressure (SBP), heart rate (HR), and mean arterial pressure (MAP) within 4 hours of administration. Secondary end points included change in vasopressor and adjunct sedative medication requirements, achievement of Richmond-Agitation Sedation Scale (RASS) 0 to −1, and incidence of cardiac arrhythmias. Results: A total of 39 patients encompassing 107 IV chlorpromazine administrations were included. The median dose was 25 mg. Median vital signs prior to infusion were SBP 129 mm Hg, HR 90 beats/minute, and MAP 88 mm Hg. Over the subsequent 4 hours, SBP and HR did not change significantly ( P = .83 and P = .10, respectively). Mean arterial pressure decreased from a median of 88 to 83 mm Hg ( P = .04). There were no significant changes in vasopressor requirements, adjunct sedative medication requirements, or achievement of RASS goal. No patients developed symptomatic cardiac arrhythmias. Conclusion: In our small retrospective study, the use of IV chlorpromazine at routine doses did not result in clinically significant hemodynamic changes when infused at a rate of 1 mg/min. Intravenous chlorpromazine may be considered as a potential treatment option for agitation in ICU patients with appropriate monitoring.
Increased subchondral bone thickness in hips with cam-type femoroacetabular impingement
Authors: Bieri Martina , Beck Martin , Limacher Andreas , Wyatt Michael C , Leunig Michael , Jüni Peter , Reichenbach Stephan 
Published: December 2018

Objectives: Increased thickness of subchondral acetabular bone with associated articular cartilage thinning in hips with femoroacetabular (FAI) cam impingement has been observed on magnetic resonance imaging (MRI). Dynamic attrition by the cam deformity moving into the acetabulum may potentiate trans-articular shear stresses thus causing these subchondral bone changes. We aimed to quantify the hypertrophic changes of subchondral acetabular bone in patients with cam-type FAI. Methods: MRI studies were performed on an asymptomatic population of young Swiss army recruits. Subjects underwent clinical examination and completed questionnaires before undergoing an MRI of the hip. Cam deformities were graded and the dimensions of the acetabular subchondral bone quantified. Univariate linear regression was used to determine the association between the presence of cam deformities and the degree of subchondral acetabular sclerosis. Results: There was a strong association between cam deformities and the thickness, area and shape of subchondral sclerosis. The main increase in hypertrophy was observed in the antero-superior acetabulum where impingement typically occurs. The subchondral sclerosis was 0.66 mm thicker in cam-type deformities than in hips without cam-type deformities (95% CI, 0.38–0.93, p value < 0.001). Conclusions: Mechanical stress in the antero-superior acetabular area is elevated in hips with a cam-type deformity. The study supports the concept that cam-type deformity induced stress leads to hypertrophy of subchondral acetabular bone in the area of impingement. This is collocated with the clinically observed cartilage damage caused by the cam mechanism.
Improving spatial working memory in blind and sighted youngsters using programmable tactile displays
Authors: Leo Fabrizio , Tinti Carla , Chiesa Silvia , Cavaglià Roberta , Schmidt Susanna , Cocchi Elena , Brayda Luca 
Published: December 2018

Objective: To investigate whether training with tactile matrices displayed with a programmable tactile display improves recalling performance of spatial images in blind, low-vision and sighted youngsters. To code and understand the behavioral underpinnings of learning two-dimensional tactile dispositions, in terms of spontaneous exploration strategies. Methods: Three groups of blind, low-vision and sighted youngsters between 6 and 18 years old performed four training sessions with a weekly schedule in which they were asked to memorize single or double spatial layouts, featured as two-dimensional matrices. Results: Results showed that all groups of participants significantly improved their recall performance compared to the first session baseline in the single-matrix task. No statistical difference in performance between groups emerged in this task. Instead, the learning effect in visually impaired participants is reduced in the double-matrix task, whereas it is still robust in blindfolded sighted controls. We also coded tactile exploration strategies in both tasks and their correlation with performance. Sighted youngsters, in particular, favored a proprioceptive exploration strategy. Finally, performance in the double-matrix task negatively correlated with using one hand and positively correlated with a proprioceptive strategy. Conclusion: The results of our study indicate that blind persons do not easily process two separate spatial layouts. However, rehabilitation programs promoting bi-manual and proprioceptive approaches to tactile exploration might help improve spatial abilities. Finally, programmable tactile displays are an effective way to make spatial and graphical configurations accessible to visually impaired youngsters and they can be profitably exploited in rehabilitation.
Influence of HIV Infection on the Natural History of Hepatocellular Carcinoma: Results From a Global Multicohort Study
Authors: Pinato David J. , Allara Elias , Chen Ting-Yi , Trevisani Franco , Minguez Beatriz , Zoli Marco , Harris Marianne , Dalla Pria Alessia , Merchante Nicolás , Platt Heather , Jain Mamta , Caturelli Eugenio , Kikuchi Luciana , Pineda Juan , Nelson Mark , Farinati Fabio , Rapaccini Gian Ludovico , Aytaman Ayse , Yin Michael , Tan Chee-Kiat , Bower Mark , Giannini Edoardo G. , Bräu Norbert ,   the Liver Cancer in HIV and ITA.LI.CA Study Groups
Published: December 2018

PURPOSE Conflicting evidence indicates that HIV seropositivity may influence the outcome of patients with hepatocellular carcinoma (HCC), a leading cause of mortality in people with HIV. We aimed to verify whether HIV affected the overall survival (OS) of patients with HCC, independent of treatment and geographic origin. PATIENTS AND METHODS We designed an international multicohort study of patients with HCC accrued from four continents who did not receive any anticancer treatment. We estimated the effect of HIV seropositivity on patients’ OS while accounting for common prognostic factors and demographic characteristics in uni- and multivariable models. RESULTS A total of 1,588 patients were recruited, 132 of whom were HIV positive. Most patients clustered within Barcelona Clinic Liver Cancer (BCLC) C or D criteria (n = 1,168 [74%]) and Child-Turcotte-Pugh (CTP) class B (median score, 7; interquartile range [IQR], 3). At HCC diagnosis, the majority of patients who were HIV-positive (n = 65 [64%]) had been on antiretrovirals for a median duration of 8.3 years (IQR, 8.59 years) and had median CD4+ cell counts of 256 (IQR, 284) with undetectable HIV RNA (n = 68 [52%]). OS decreased significantly throughout BCLC stages 0 to D (16, 12, 7.5, 3.1, and 3 months, respectively; P < .001). Median OS of patients who were HIV-positive was one half that of their HIV-uninfected counterparts (2.2 months [bootstrap 95% CI, 1.2 to 3.1 months] v 4.1 months [95% CI, 3.6 to 4.4 months]). In adjusted analyses, HIV seropositivity increased the hazard of death by 24% ( P = .0333) independent of BCLC ( P < .0001), CTP ( P < .0001), α-fetoprotein ( P < .0001), geographical origin ( P < .0001), and male sex ( P = .0016). Predictors of worse OS in patients who were HIV-positive included CTP ( P = .0071) and α-fetoprotein ( P < .0001). CONCLUSION Despite adequate antiretroviral treatment, HIV seropositivity is associated with decreased survival in HCC, independent of stage, anticancer treatment, and geographical origin. Mechanistic studies investigating the immunobiology of HIV-associated HCC are urgently required.
The contribution of industrial minerals to solving environmental issues
Authors: Calvo Jose P. , Garcia-Lorenzo Mari Luz 
Published: December 2018

Mitigation of environmental issues and decontamination of land by using a variety of industrial minerals mainly immobilizes contaminants in solution, whether in polluted water or contaminated soils and sediments. That is because a variety of minerals, in particular carbonates, clays and zeolites, have a significant capacity to ad/absorb harmful ions and to react to form precipitates. Phosphates, iron hydroxides, some silica minerals and lime-derived products can also be used to solve environmental issues. This paper focuses on the amendment of soils and sediments affected by the impact of mining or by waste landfills, with some reference to the use of minerals in cultural heritage conservation. An example of actions leading to the amelioration of contaminated land is provided after describing some current pilot experiences on highly polluted wastes derived from mining in SE Spain.
Reliability and validity of non-radiological measures of thoracic kyphosis in chronic obstructive pulmonary disease
Authors: Lee Annemarie L , Goldstein Roger S , Rhim Matthew , Chan Christen , Brooks Dina , Zabjek Karl 
Published: December 2018

Background/Aims: Thoracic kyphosis in people with chronic obstructive pulmonary disease can be measured from digital photogrammetry or three-dimensional motion capture. This study aimed to determine the reliability, validity and agreement for non-radiological measures of thoracic kyphosis in chronic obstructive pulmonary disease. Methods: A total of 19 participants with chronic obstructive pulmonary disease were included. Cobb angles from chest radiographs and spinous process landmarks using photogrammetry and three-dimensional motion capture were evaluated. Findings: The mean kyphosis (± standard deviation) was 48.8 ± 10.9 degrees by radiograph; 49.6 ± 12.9 degrees by three-dimensional motion capture and 52.2 ± 11.1 degrees by photogrammetry. Radiographic Cobb angle and photogrammetry measurements demonstrated excellent intra- and inter-rater reliability. Correlation between non-radiological kyphosis measurements and chest radiographs was strong (Pearson's r2 >0.75 for both). Limits of agreement between radiographs and 3D motion capture were –9 degrees to 7 degrees, and –12 to 8 degrees between radiographs and photogrammetry. Conclusions: Non-radiological measures of thoracic kyphosis are reliable and valid in chronic obstructive pulmonary disease.
Thwarting Plagiarism in the Humanities Classroom: Storyboards, Scaffolding, and a Death Fair
Authors: Hale Mary 
Published: December 2018

Best practices research on plagiarism in the University classroom shows that modifying assignments and classroom environment can have a positive effect on lowering a student’s desire to cheat. James Lang suggests four features of a learning environment that can be fostered to ameliorate a student’s desire to cheat: mastery of the material for its own sake, low-stakes assignments, intrinsic motivations for learning and, a high expectation of success. Scaffolding has been shown to be a useful pedagogical technique for empowering students (fostering a high expectation of success) My past experience using a variety of visual classroom exercises (cartooning, mind-mapping, advertising campaigns, etc.) gave anecdotal evidence that artistic and visual assignments encouraged a level of engagement and collaboration across language and cultural boundaries not experienced in other types of assignments. I hypothesized that this level of engagement and collaboration could be used with scaffolding to motivate Lang’s four features and experimented with the use of poster presentations and other visual and spatial assignments in a second year undergraduate Religious Studies course on Death. Very preliminary qualitative data support the hypothesis that, by addressing Lang’s four features and incorporating scaffolding and visual assignments into the course, students are cheating less and learning more. This research strengthens the extant literature on the impact class environment and expectations have on plagiarism while also adding to the growing body of literature supporting the use of visual assignments, such as poster presentations, mind mapping, and storyboards in the Arts and Humanities.
How Europe should Overcome the Coming Deadlock
Authors: Chortareas Georgios , Pelagidis Theodore 
Published: December 2018

Abstract
This note discusses the implications of deadlocks in the European Union in the light of the evolution of EU institutions during and after the recent economic crisis. We highlight the challenge of avoiding deadlocks without resorting to the expulsion threat. The need to accelerate “convergence in institutions” among the Union members emerges.