bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association Between Soluble Notch Ligand Delta-like Ligand 1 and Bleeding Complications in Patients With Dengue Fever Infection
Authors: Hildebrand Dagmar , Nurjadi Dennis , Hoan Nghiem Xuan , Linh Mai Thanh Hai , Sang Vu Viet , Bang Mai Hong , Pallerla Srinivas Reddy , Kremsner Peter G , Heeg Klaus , Song Le Huu , Velavan Thirumalaisamy P 
Published: August 2021

Abstract
Bleeding associated with endothelial damage is a key feature of severe dengue fever. In the current study, we investigated whether Notch ligands were associated with bleeding in 115 patients with confirmed dengue infection in Vietnam. Soluble Notch ligands were determined by means of enzyme-linked immunosorbent assay. Seventeen of 115 patients (14.8%) experienced bleeding manifestations. High soluble delta-like ligand 1 (sDLL1) plasma levels was associated with bleeding (median, 15 674 vs 7117 pg/mL; P &lt; .001). Receiver operating characteristic (ROC) curve analysis demonstrated that sDLL1 had the best test performance (area under the ROC curve, 0.852), with 88% sensitivity and 84% specificity. The combination with alanine aminotransferase and aspartate aminotransferase slightly increased sDLL1 performance. sDLL1 may be useful to guide clinical management of patients with patients in endemic settings.
Engineering strategies for broad application of TCR-T- and CAR-T-cell therapies
Authors: Watanabe Keisuke , Nishikawa Hiroyoshi 
Published: August 2021

AbstractAdoptive-cell therapy, including the transfer of tumor-infiltrating T lymphocytes after in vitro expansion or T cells redirected to tumor antigens using antigen-specific transgenic T-cell receptor T cells (TCR-T cells) or chimeric antigen receptor T cells (CAR-T cells), has shown a significant clinical impact. Particularly, several types of CAR-T-cell therapies have been approved for the treatment of hematological malignancies. The striking success of CAR-T-cell therapies in hematological malignancies motivates their further expansion to a wide range of solid tumors, yet multiple obstacles, including the lack of proper target antigens exhibiting a tumor-specific expression pattern and the immunosuppressive tumor microenvironment (TME) impairing the effector functions of adoptively transferred T cells, have prevented clinical application. Gene engineering technologies such as the CRISPR/Cas9 system have enabled flexible reprogramming of TCR/CAR-T-cell signaling or loading genes that are targets of the tumor immunosuppression as a payload to overcome the difficulties. Here, we discuss recent advances in TCR/CAR-T-cell engineering: various promising approaches to enhance the anti-tumor activity of adoptively transferred T cells in the TME for maximizing the efficacy and the safety of adoptive-cell therapy are now being tested in the clinic, especially targeting solid tumors.
Effect of nationwide concurrent drug utilization review program on drug–drug interactions and related health outcome
Authors: Kim Dong-Sook , Je Nam Kyung , Park Juhee , Lee Sukhyang 
Published: August 2021

Abstract

Background
A computerized drug utilization review (DUR) program has provided physicians and pharmacists with alerts on drug–drug interactions (DDIs), drug–age precautions and therapeutic duplication in Korea since 2010.

Objective
The purpose of this study was to evaluate the impact of the DUR program on health outcomes associated with DDIs.

Methods
An uncontrolled before–after study was performed to investigate the impact of the nationwide DUR program on DDIs and related health outcomes. The study population consisted of people who used two types of DDI pairs before DUR implementation (from January 2009 to December 2010) and post-DUR implementation (from January 2012 to December 2013); (i) benzodiazepines with concurrent use of metabolic enzyme inhibitors and (ii) QTc (heart-rate corrected QT interval) prolongation agents. The main outcome measures were all-cause and cause-specific hospitalization admissions or emergency department (ED) visits.

Results
This study included 107 874 people who used benzodiazepines with enzyme inhibitors and 8489 who received co-medication of QTc prolongation agents. For patients receiving a combination of benzodiazepines and enzyme inhibitors, both all-cause hospitalization and cause-specific hospitalization decreased after DUR implementation, from 43.2% to 41.7% and from 4.6% to 4.5% (adjusted odds ratio [OR] = 0.96; 95% confidence interval (CI), 0.93–0.98; OR = 0.89, 95% CI = 0.84–0.99, respectively). For patients receiving co-medication of QTc prolongation agents, all-cause hospitalization (54.2%) was lower than before (54.9%) (OR = 0.87, 95% CI = 0.79–0.96), but no significant change was found for cause-specific hospitalization and ED visits.

Conclusion
Implementation of a DUR program may reduce the adverse health outcomes posed by DDIs in patients on combination of benzodiazepines and enzyme inhibitors potentially QTc-prolongation agents.
An inexpensive, simple and effective method of genome DNA fragmentation for NGS libraries
Authors: Kechin Andrey , Boldyreva Darya , Borobova Viktoriya , Boyarskikh Ulyana , Scherbak Sergey , Apalko Svetlana , Makarova Maria , Mosyakin Nikolay , Kaftyreva Lidia , Filipenko Maxim 
Published: August 2021

Abstract
Next-generation sequencing (NGS)-library preparation for whole-genome sequencing (WGS) starts with DNA fragmentation, and sonication is a physical approach used most often due to its simplicity and reproducibility. However, the commercially available Covaris instrument has a high price for both the device and consumables. Here, we describe our in-house method of DNA shearing by sonication with small (100–600 µm) glass beads and an ultrasonic bath. The fragmentation conditions were optimized for the bacterial WGS with ∼550-bp fragment size (the ultrasonic bath water temperature 5–10°C, glass beads 0.06 g, the fragmentation time 50 s) and for human DNA with ∼250 bp (fragmentation with the same parameters for 4 min). Fragmentation results were compared with the Covaris instrument for preparing several bacterial NGS libraries for Illumina NGS platforms by several characteristics. We obtained close mean fragment lengths (523–623 versus 480–646), similar mono- and dinucleotide specificity of shearing, and comparable indicators of read alignment and de novo assembly for both methods. Thus, the described method is a new fast, and effective DNA fragmentation approach that can be used in different WGS applications.
Shaping REDD+: Interactions between Bilateral and Multilateral Rulemaking
Authors: Recio María Eugenia 
Published: August 2021

Abstract
This article studies bilateral partnerships on reducing emissions from deforestation and forest degradation (REDD+), particularly those led by Norway, through the conceptual lens of legal diffusion. The article argues that rules created through such partnerships have significantly influenced rulemaking under the United Nations Framework Convention on Climate Change. It shows that bilaterally developed rules have spread to other countries beyond the original partners, particularly in respect of topics such as financial institutional structures and a results-based approach to REDD+. Reciprocal legal influence between multilateral and bilateral legal developments can further be seen in relation to other topics, such as monitoring, reporting and verification. The article shows that legal concepts related to REDD+ travelled in different directions, showcasing interactions between bilateral and multilateral arenas in the construction of international norms, as well as interactions between the law for environmental protection and development cooperation.
3D finite-element modeling of effective elastic properties for fracture density and multiscale natural fractures
Authors: Jian Shikai , Fu Li-Yun , Cao Chenghao , Han Tongcheng , Du Qizhen 
Published: August 2021

AbstractNatural fractures are usually multiscale in size, orientations and distribution, resulting in complex anisotropic characteristics. Analytical methods for quantifying the associated effective elastic properties are based on some assumptions, such as dilute fracture concentration and regular-shaped fractures, which do not occur in actual reservoirs. Here, we conduct anisotropic finite-element modeling of effective elastic properties of complex fractured rocks using the least-square fitting method. The algorithm is developed for a 3D case and validated by classical effective medium theories for models with different fracture densities. The results of the 3D numerical method agree well with the theoretical predictions at low fracture density. The model also considers the interactions among fractures to calculate equivalent stiffness tensors at high fracture density. Three 2D fracture models are simulated to demonstrate the basic behavior of stress interactions and their effect on the overall elasticity under different fracture densities. We applied the developed model to 3D natural fractures built from a real outcrop, and we found that the fracturing pattern significantly affects the effective anisotropy properties. The resultant P-wave phase velocities as functions of the incidence angle and frequency are anisotropic. This study provides a great potential to calculate equivalent stiffness tensors and anisotropic properties of 3D multiscale natural fractures.
Reflective Willingness to Pay: Preferences for Sustainable Consumption in a Consumer Welfare Analysis
Authors: Inderst Roman , Thomas Stefan 
Published: August 2021

Abstract
Our starting point is the following simple but potentially underappreciated observation: When assessing willingness to pay (WTP) for hedonic features of a product, the results of such measurement are influenced by the context in which the consumer makes her real or hypothetical choice or in which the questions to which she replies are set (such as in a contingent valuation analysis). This observation is of particular relevance when WTP regards sustainability, the ‘non-use value’ of which does not derive from a direct (physical) sensation and where perceived benefits depend heavily on available information and deliberations. The recognition of such context sensitivity paves the way for a broader conception of consumer welfare (CW), and our proposed standard of ‘reflective WTP’ may materially change the scope for private market initiatives with regards to sustainability, while keeping the analytical framework within the realm of the CW paradigm. In terms of practical implications, we argue, for instance, that actual purchasing decisions may prove insufficient to measure consumer appreciation of sustainability, as they may rather echo learnt but unreflected heuristics and may be subject to the specific shopping context, such as heavy price promotions. Also, while preferences may reflect the current social norm, the latter may change considerably over time as more consumers adapt their behaviour.
DIGITAL MARKET DEFINITION IN THE EUROPEAN UNION, UNITED STATES, AND BRAZIL: PAST, PRESENT, AND FUTURE
Authors: Eben Magali , Robertson Viktoria H S E 
Published: August 2021

Abstract
Market definition is a core concept of competition law around the globe, including in the European Union, the United States, and Brazil. In all three jurisdictions, antitrust authorities are grappling with the challenges of digital markets, often dealing with the very same digital players. The provision of zero-price services, the multisided nature of many digital platforms, and the implementation of entire digital ecosystems all challenge traditional approaches to market definition. But where there are common problems, there is a potential for common solutions. Through a comparative analysis of decisional practice relating to these past, present, and future challenges of digital market definition, this contribution maps the common ground already achieved while highlighting remaining gaps and possible solutions: for zero-price services—the past—it shows how a consensus has emerged on the theory and possible tools to define markets for ‘free’ services. On multisided platforms—the present—it finds that no such consensus has been reached yet, but strides are currently being made in developing an overall framework. And on digital ecosystems, it analyses how this challenge of the future requires the development of a coherent approach that can be based on cross-jurisdictional insights from the past and present.
Comparative Effectiveness of Echinocandins vs Triazoles or Amphotericin B Formulations as Initial Directed Therapy for Invasive Candidiasis in Children and Adolescents
Authors: Fisher Brian T , Zaoutis Theoklis E , Xiao Rui , Wattier Rachel L , Castagnola Elio , Pana Zoi Dorothea , Fullenkamp Allison , Boge Craig L K , Ross Rachael K , Yildirim Inci , Palazzi Debra L , Danziger-Isakov Lara , Vora Surabhi B , Arrieta Antonio , Yin Dwight E , Avilés-Robles Martha , Sharma Tanvi , Tribble Alison C , Maron Gabriela , Berman David , Green Michael , Sung Lillian , Romero José , Hauger Sarmistha B , Roilides Emmanuel , Belani Kiran , Nolt Dawn , Soler-Palacin Pere , López-Medina Eduardo , Muller William J , Halasa Natasha , Dulek Daniel , Hussain Ibrahim Zaid Bin , Pong Alice , Hoffman Jill , Rajan Sujatha , Gonzalez Blanca E , Hanisch Benjamin , Aftandilian Catherine , Carlesse Fabianne , Abzug Mark J , Huppler Anna R , Salvatore Christine M , Ardura Monica I , Chakrabarti Arunaloke , Santolaya Maria E , Localio A Russell , Steinbach William J 
Published: August 2021

Abstract

Background
Invasive candidiasis is the most common invasive fungal disease in children and adolescents, but there are limited pediatric-specific antifungal effectiveness data. We compared the effectiveness of echinocandins to triazoles or amphotericin B formulations (triazole/amphotericin B) as initial directed therapy for invasive candidiasis.

Methods
This multinational observational cohort study enrolled patients aged &gt;120 days and &lt;18 years with proven invasive candidiasis from January 1, 2014, to November 28, 2017, at 43 International Pediatric Fungal Network sites. Primary exposure was initial directed therapy administered at the time qualifying culture became positive for yeast. Exposure groups were categorized by receipt of an echinocandin vs receipt of triazole/amphotericin B. Primary outcome was global response at 14 days following invasive candidiasis onset, adjudicated by a centralized data review committee. Stratified Mantel-Haenszel analyses estimated risk difference between exposure groups.

Results
Seven-hundred and fifty invasive candidiasis episodes were identified. After exclusions, 541 participants (235 in the echinocandin group and 306 in the triazole/amphotericin B group) remained. Crude failure rates at 14 days for echinocandin and triazole/amphotericin B groups were 9.8% (95% confidence intervals [CI]: 6.0% to 13.6%) and 13.1% (95% CI: 9.3% to 16.8%), respectively. The adjusted 14-day risk difference between echinocandin and triazole/amphotericin B groups was −7.1% points (95% CI: −13.1% to −2.4%), favoring echinocandins. The risk difference was −0.4% (95% CI: −7.5% to 6.7%) at 30 days.

Conclusions
In children with invasive candidiasis, initial directed therapy with an echinocandin was associated with reduced failure rate at 14 days but not 30 days. These results may support echinocandins as initial directed therapy for invasive candidiasis in children and adolescents.

Clinical Trials Registration
NCT01869829.
Spatial statistics in star-forming regions: is star formation driven by column density alone?
Authors: Retter B , Hatchell J , Naylor T 
Published: August 2021

ABSTRACT
Star formation is known to occur more readily where more raw materials are available. This is often expressed by a ‘Kennicutt–Schmidt’ relation where the surface density of young stellar objects (YSOs) is proportional to column density to some power, μ. The aim of this work was to determine if column density alone is sufficient to explain the locations of Class 0/I YSOs within Serpens South, Serpens Core, Ophiuchus, NGC 1333, and IC348, or if there is clumping or avoidance that would point to additional influences on the star formation. Using the O-ring test as a summary statistic, 95 per cent confidence envelopes were produced for different values of μ from probability models made using the Herschel column density maps. The YSOs were tested against four distribution models: the best estimate of μ for the region, μ = 0 above a minimum column density threshold, and zero probability elsewhere, μ = 1, and the power law that best represents the five regions as a collective, μ = 2.05 ± 0.20. Results showed that μ = 2.05 model was consistent with the majority of regions and, for those regions, the spatial distribution of YSOs at a given column density is consistent with being random. Serpens South and NGC 1333 rejected the μ = 2.05 model on small scales of ${\sim}0.15\, \mathrm{pc}$ which implies that small-scale interactions may be necessary to improve the model. On scales above 0.15 pc, the positions of YSOs in all five regions can be well described using column density alone.
MLTI-06. Surgical resection plus stereotactic radiosurgery versus SRS alone for large brain metastases: a comparative study
Authors: Gutierrez Enrique , Kalyvas Aristotelis , Villafuerte Conrad , Millar Barbara-Ann , Conrad Tatiana , Laperriere Normand , Bernstein Mark , Weiss Jessica , Zadeh Gelareh , Kongkham Paul , Shultz David 
Published: August 2021

Abstract

Purpose
Large brain metastases (BRM) are challenging to manage. Therapeutic options include Stereotactic Radiosurgery (SRS) or surgery (S) with adjuvant SRS. We sought to compare overall survival (OS), radionecrosis (RN), local failure (LF), pachymeningeal (PMD) and leptomeningeal (LMD) disease in patients treated with SRS vs. S+SRS.

Methods
We reviewed a prospective registry database from 2009 to 2020 and identified all patients with BRM (≥4cc in volume) treated with SRS or S+SRS. WBRT or SRS re-targeting the index lesion were censoring events. Survival percentages were calculated using the Kaplan-Meier method. Differences between groups were tested using the Cox proportional hazards model.

Results
383 patients were identified, 128 and 255 were treated with S+SRS and SRS, respectively. Median ages in the S+SRS and SRS groups were 62.2 (23.6–98.5) and 60.2 (20.2–97.4) (P 0.33). OS at 12 and 24 months was 69% and 41% vs 55% and 20% for the S+SRS and SRS groups, respectively hazard ratio (HR) 1.64 (1.23–2.18) (P&lt;0.001). LF requiring salvage surgery at 12 and 24 months were 3% and 5% vs 8% and 10% for S+SRS and SRS groups, respectively (P 0.067). RN at 12 and 24 months were 9% and 17% vs 15% and 21% for S+SRS and SRS groups, respectively 1.32 HR (0.77–2.29) (P =0.32). PMD disease at 12 and 24 months were 16% and 21% vs 3% and 7% for S+SRS and SRS groups, respectively HR 0.26(0.12–0.56) (P &lt; 0.001). LMD at 12 and 24 months were 4% and 6% vs 2% and 4% for S+SRS and SRS groups, respectively HR 0.73(0.25–2.17) (P 0.57).

Conclusion
Surgical resection plus SRS correlated with improved OS and a trend towards a decreased incidence of LF compared to SRS alone. However, patients treated with S experienced an increased incidence of PMD.
OTHR-14. An immunogenomic analysis of melanoma brain metastases (MBM) compared to extracranial metastases (ECM)
Authors: Kennedy Lucy Boyce , Van Swearingen Amanda E D , Sheng Jeff , Zhang Dadong , Qin Xiaodi , Lipp Eric , Kumar Swaminathan , Zhang Gao , Hanks Brent , Davies Michael , Owzar Kouros , Anders Carey K , Salama April K S 
Published: August 2021

Abstract

Background
MBM have a unique molecular profile compared to ECM.

Methods
We analyzed a previously published dataset from MD Anderson Cancer Center, including RNA-seq on surgically resected, FFPE MBM and ECM from the same patients. STAR pipeline was used to estimate mRNA abundance. DESeq2 package was used to perform differential gene expression (DGE) analyses. Pathway analysis was performed using Gene Set Enrichment Analysis (GSEA). Paired DGE and GSEA compared MBM vs. lymph node (LN) metastases (n = 16) and MBM vs. skin mets (n = 10). CIBERSORTx estimated relative abundance of immune cell types in MBM and ECM. GATK Mutect2 pipeline was used to call somatic mutations using paired normal tumor samples. Mutations were annotated using the Ensembl Variant Effect Predictor and visualized using the Maftools package in R.
RNA-seq was available on 54 human primary cutaneous melanomas (CM). Gene Ontology or KEGG Pathway analysis was performed using goana function of limma package in R.

Results
Paired GSEA found that autophagy pathways may be up-regulated in MBM vs. LN and MBM vs. skin mets. On a single-gene level, the most strongly up-regulated genes in autophagy pathways were GFAP and HBB. Fold changes in other autophagy-related genes were low and did not reach significance. Comparison between CM which recurred in brain vs. CM which did not recur identified up-regulation of autophagy pathways. CIBERSORTx identified an increased proportion of immune suppressive M2 macrophages compared to tumor suppressive M1 macrophages in MBMs and ECMs.

Conclusion
Up-regulation of autophagy pathways was observed in patient-matched MBM vs. LN and skin mets. This finding was driven by up-regulation of GFAP and HBB, which could reflect changes in the tumor microenvironment. Higher M2:M1 ratio may contribute to an immune suppressive tumor microenvironment and may be targetable. Validation of our findings in an independent Duke dataset is ongoing.
RADI-07. Individualized Nomogram for Predicting Survival of Patients with Brain Metastases after Stereotactic Radiosurgery
Authors: Wen Lei , Shan Changguo , Lai Mingyao , Zhou Zhaoming , Cai Linbo 
Published: August 2021

Abstract

Background
Given the increasing use of stereotactic radiosurgery (SRS) for brain metastases (BM), there is an emerging need for more precise assessment of survival outcomes after SRS, especially in the modern targeted therapy era.

Methods
Patients with BM and treated by SRS were eligible in this study. Primary endpoint was overall survival (OS). Cox models were used to identify independent prognostic factors. Survival predictive nomogram was developed and evaluated by Concordance-index (C-index), area under the curve (AUC) and calibration curve.

Results
From January 2016 to December 2019, a total of 356 BM patients were eligible. Median OS was 17.7 months (95%CI 15.5–19.9) and actual OS at 1- and 2-year measured 63.2% and 37.6%, respectively. Nomogram for OS was developed by incorporating four independent prognostic factors: Karnofsky Performance Score, cumulative tumor volume, driver gene mutation status and serum lactate dehydrogenase. The nomogram was validated in a separate cohort demonstrated a well calibration and good discriminative ability (C-index=0.780, AUC=0.784). The prognostic accuracy of the nomogram (0.792) was considerably enhanced compared with classical prognostic indices, i.e., GPA (0.708), RPA (0.587) and SIR (0.536). Kaplan-Meier curves showed significant difference of OS among stratified low-, median- and high-risk groups (P &lt; .001).

Conclusion
In conclusion, we developed and validated an individualized prognostic nomogram by integrating physiological, volumetric, clinical chemistry and molecular biological surrogates. This nomogram, should be validated by independent external study, has a potential to facilitate more precise risk-stratifications to guide personalized treatment for BM.