bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bacterial-Driven Inflammation and Mutant BRAF Expression Combine to Promote Murine Colon Tumorigenesis That Is Sensitive to Immune Checkpoint Therapy
Authors: DeStefano Shields Christina E. , White James R. , Chung Liam , Wenzel Alyssa , Hicks Jessica L. , Tam Ada J. , Chan June L. , Dejea Christine M. , Fan Hongni , Michel John , Maiuri Ashley R. , Sriramkumar Shruthi , Podicheti Ram , Rusch Douglas B. , Wang Hao , De Marzo Angelo M. , Besharati Sepideh , Anders Robert A. , Baylin Stephen B. , O'Hagan Heather M. , Housseau Franck , Sears Cynthia L. 
Published: February 2021

Abstract

Colorectal cancer is multifaceted, with subtypes defined by genetic, histologic, and immunologic features that are potentially influenced by inflammation, mutagens, and/or microbiota. Colorectal cancers with activating mutations in BRAF are associated with distinct clinical characteristics, although the pathogenesis is not well understood. The Wnt-driven multiple intestinal neoplasia (MinApcΔ716/+) enterotoxigenic Bacteroides fragilis (ETBF) murine model is characterized by IL17-dependent, distal colon adenomas. Herein, we report that the addition of the BRAFV600E mutation to this model results in the emergence of a distinct locus of midcolon tumors. In ETBF-colonized BRAFV600ELgr5CreMin (BLM) mice, tumors have similarities to human BRAFV600E tumors, including histology, CpG island DNA hypermethylation, and immune signatures. In comparison to Min ETBF tumors, BLM ETBF tumors are infiltrated by CD8+ T cells, express IFNγ signatures, and are sensitive to anti–PD-L1 treatment. These results provide direct evidence for critical roles of host genetic and microbiota interactions in colorectal cancer pathogenesis and sensitivity to immunotherapy.

Significance:
Colorectal cancers with BRAF mutations have distinct characteristics. We present evidence of specific colorectal cancer gene–microbial interactions in which colonization with toxigenic bacteria drives tumorigenesis in BRAFV600ELgr5CreMin mice, wherein tumors phenocopy aspects of human BRAF-mutated tumors and have a distinct IFNγ-dominant immune microenvironment uniquely responsive to immune checkpoint blockade.
This article is highlighted in the In This Issue feature, p. 1601
Single-Cell Transcriptomic Atlas of Different Human Cardiac Arteries Identifies Cell Types Associated With Vascular Physiology
Authors: Hu Zhan , Liu Wendao , Hua Xiumeng , Chen Xiao , Chang Yuan , Hu Yiqing , Xu Zhenyu , Song Jiangping 
Published: February 2021

Objective:
Although cellular heterogeneity within arterial walls has been explored in mice and nonhuman primates, the cellular composition of human arterial walls remains unclear.

Approach and Results:

The cellular composition of nondiseased cardiac arteries (3 aortas, 2 pulmonary arteries and 9 coronary arteries) from 3 heart transplantation patients were investigated by single-cell sequencing of >10
5
cells. Clustering analysis identified 25 subpopulations representing the 10 main arterial cell types: vascular smooth muscle cell (4 clusters), fibroblast (4 clusters), macrophage (Mφ, 4 clusters), T cell (4 clusters), endothelial cell (4 clusters), NK cell (2 clusters), mast cell (1 cluster), myofibroblast (1 cluster), oligodendrocyte (1 cluster), and B/plasma cells (1 cluster). Vascular smooth muscle cell was the largest cell population in cardiac arteries, followed by fibroblast, Mφ, T cell, endothelial cell, NK cell, and so on. We compared cellular composition among different arteries and found some artery-specific vascular smooth muscle cell and fibroblast subpopulations. The communication between vascular smooth muscle cell and fibroblast was predominant in nondiseased condition. Atherosclerosis-associated genes were particularly enriched in endothelial cell and Mφ, and intercellular communication between endothelial cell and immune cells was predicted to increase in atherosclerosis. The interaction between
ICAM1
/
VCAM1
(EC1) and
ITGB2
(immune cells, especially inflammatory Mφ) was speculated to be essential for the pathogenesis of atherosclerosis.

Conclusions:
We created a cell atlas of human nondiseased cardiac arteries, and characterized the cellular compositions in different cardiac arteries. Our results could be used as a reference to identify vascular disease-associated cell populations and help investigate new therapeutic strategies for vascular diseases.
Vascular Endothelial Damage in the Pathogenesis of Organ Injury in Severe COVID-19
Authors: Dupont Annabelle , Rauch Antoine , Staessens Senna , Moussa Mouhamed , Rosa Mickael , Corseaux Delphine , Jeanpierre Emmanuelle , Goutay Julien , Caplan Morgan , Varlet Pauline , Lefevre Guillaume , Lassalle Fanny , Bauters Anne , Faure Karine , Lambert Marc , Duhamel Alain , Labreuche Julien , Garrigue Delphine , De Meyer Simon F. , Staels Bart , Vincent Flavien , Rousse Natacha , Kipnis Eric , Lenting Peter , Poissy Julien , Susen Sophie ,   the Lille Covid Research Network (LICORNE)
Published: February 2021

Objective:
Whether endotheliopathy only mirrors coronavirus disease 2019 (COVID-19) severity or plays an intrinsic role in microvascular thrombosis and organ failure remains unanswered. We assessed whether markers of endothelial damage and immune dysregulation were associated with organ failure, thrombus formation, and death.

Approach and Results:
Markers of endothelial damage (VWF:Ag [von Willebrand factor antigen], PAI-1 [plasminogen activator inhibitor-1], syndecan-1, TFPI [tissue factor pathway inhibitor], and soluble thrombomodulin), complement activation (C5a and C5b-9), cytokines (IL [interleukin]-6, TNF [tumor necrosis factor]-α, and IL-2R), and neutrophil extracellular traps (cell-free DNA, nucleosomes, and myeloperoxidase-DNA) were measured at intensive care unit admission in 82 patients with COVID-19. We also analyzed the histological composition of thrombi collected in critically ill living patients successfully weaned from extracorporeal membrane oxygenation. Beside respiratory failure, VWF:Ag, PAI-1, TFPI, and syndecan-1 were independently associated with liver injury and multiorgan failure development, underlining the direct role of endotheliopathy in organ failure. Nucleosomes were also associated with liver injury, multiorgan failure, and death which occurred in 38%, 60%, and 27% of patients, respectively. Moreover, dysregulated immune response including cytokines, complement, and neutrophil extracellular traps was associated with markers of endothelial damage, respiratory failure, and liver injury. COVID-19 thrombi retrieved from extracorporeal membrane oxygenation circuitry contained accumulation of neutrophils, VWF, and significantly higher amount of neutrophil extracellular traps when compared with non-COVID-19 thrombi.

Conclusions:
We provide new associative data supporting that endotheliopathy and dysregulated immune responses are involved in respiratory and liver failure through microvascular damage in patients with severe COVID-19.
Reelin Depletion Protects Against Atherosclerosis by Decreasing Vascular Adhesion of Leukocytes
Authors: Calvier Laurent , Xian Xunde , Lee Richard G. , Sacharidou Anastasia , Mineo Chieko , Shaul Philip W. , Kounnas Maria Z. , Tsai Shirling , Herz Joachim 
Published: February 2021

Objective:
Reelin and its receptor Apoer2 (apolipoprotein E receptor 2) play a prominent role in endothelial cell dysfunction by promoting leukocyte–endothelial cell adhesion, an important component of the inflammatory process underlying atherosclerosis. We, therefore, hypothesized that pharmacological depletion of circulating reelin represents a novel therapeutic strategy to impede the progression of atherosclerosis.

Approach and Results:

In vitro studies demonstrated that human plasma induced monocyte adhesion to endothelial cells, while reelin-depleted plasma had no effect on monocyte adhesion. Signaling analysis revealed that reelin activated a Dab2, PI3K (phosphoinositide 3-kinase), Akt (protein B kinase), and NF-κB (nuclear factor κB) cascade to promote the expression of adhesion markers (E-selectin, ICAM-1 [intercellular adhesion molecule 1], and VCAM-1 [vascular cell adhesion molecule 1]). Intravital microscopy confirmed decreased leukocyte-endothelial adhesion in mice treated with reelin antisense oligonucleotide. In vascular smooth muscle cells, reelin induced Stat3 phosphorylation to promote cell proliferation, which is another hallmark of atherosclerotic plaque progression. To investigate if reelin pharmaceutical depletion protects against atherosclerosis, low-density lipoprotein receptor–deficient (
Ldlr
−/−
) mice fed with high-cholesterol diet were treated with either reelin antisense oligonucleotide or neutralizing antibody (CR-50) to systemically deplete circulating reelin. In both treatments, atherosclerotic plaque progression was markedly attenuated. These in vivo results suggest that reelin depletion decreases vascular adhesion and inhibits the recruitment of monocytes and consequently prevents plaque progression.

Conclusions:
These findings suggest that reelin inhibition may provide a novel therapeutic approach to counteract leukocyte or monocyte adhesion as well as extravasation and inhibit the progression of atherosclerosis. This strategy may also be relevant for other diseases that involve leukocyte or monocyte extravasation as a central pathological mechanism, such as multiple sclerosis or arthritis.
Coronavirus Disease 2019 Hospitalizations Attributable to Cardiometabolic Conditions in the United States: A Comparative Risk Assessment Analysis
Authors: O’Hearn Meghan , Liu Junxiu , Cudhea Frederick , Micha Renata , Mozaffarian Dariush 
Published: February 2021

BACKGROUND
Risk of coronavirus disease 2019 (COVID‐19) hospitalization is robustly linked to cardiometabolic health. We estimated the absolute and proportional COVID‐19 hospitalizations in US adults attributable to 4 major US cardiometabolic conditions, separately and jointly, and by race/ethnicity, age, and sex.

METHODS AND RESULTS

We used the best available estimates of independent associations of cardiometabolic conditions with a risk of COVID‐19 hospitalization; nationally representative data on cardiometabolic conditions from the National Health and Nutrition Examination Survey 2015 to 2018; and US COVID‐19 hospitalizations stratified by age, sex, and race/ethnicity from the Centers for Disease Control and Prevention’s Coronavirus Disease 2019–Associated Hospitalization Surveillance Network database and from the COVID Tracking Project to estimate the numbers and proportions of COVID‐19 hospitalizations attributable to diabetes mellitus, obesity, hypertension, and heart failure. Inputs were combined in a comparative risk assessment framework, with probabilistic sensitivity analyses and 1000 Monte Carlo simulations to jointly incorporate stratum‐specific uncertainties in data inputs. As of November 18, 2020, an estimated 906 849 COVID‐19 hospitalizations occurred in US adults. Of these, an estimated 20.5% (95% uncertainty interval [UIs], 18.9–22.1) of COVID‐19 hospitalizations were attributable to diabetes mellitus, 30.2% (UI, 28.2–32.3) to total obesity (body mass index ≥30 kg/m
2
), 26.2% (UI, 24.3–28.3) to hypertension, and 11.7% (UI, 9.5–14.1) to heart failure. Considered jointly, 63.5% (UI, 61.6–65.4) or 575 419 (UI, 559 072–593 412) of COVID‐19 hospitalizations were attributable to these 4 conditions. Large differences were seen in proportions of cardiometabolic risk–attributable COVID‐19 hospitalizations by age and race/ethnicity, with smaller differences by sex.

CONCLUSIONS
A substantial proportion of US COVID‐19 hospitalizations appear attributable to major cardiometabolic conditions. These results can help inform public health prevention strategies to reduce COVID‐19 healthcare burdens.
Early Apixaban Use Following Stroke in Patients With Atrial Fibrillation
Authors: Labovitz Arthur J. , Rose David Z. , Fradley Michael G. , Meriwether John N. , Renati Swetha , Martin Ryan , Kasprowicz Thomas , Murtagh Ryan , Kip Kevin , Beckie Theresa M. , Stoddard Marcus , Bozeman Andrea C. , McTigue Tara , Kirby Bonnie , Tran Nhi , Burgin W. Scott , Armanious M. , Beltagy A. , Chae S. , Chen A. , Cook C. , Edwards C. , Gooch C.L. , Glunk H. , Guerrero W. , Falcao D. , Fernandez J. , Gangadhara S. , Hermann R. , Lockwood C. , Mokin M. , Oliveira G. , Patel A. , Pendurthi A. , Pesquera J. , Ramos-Canseco J. , Shaw J. , Wick N. , Longaker R. , Webb A. , Liu W. , Korabathina R. , Delmontagne K. , Henderson T. , Mehta B , Ledesma J. , Berube K. , Cucchiara Brett , Flaker Greg , Homma Shunichi , Zgibor Janice 
Published: February 2021

Background and Purpose:
It is unknown when to start anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF). Early anticoagulation may prevent recurrent infarctions but may provoke hemorrhagic transformation as AF strokes are typically larger and hemorrhagic transformation-prone. Later anticoagulation may prevent hemorrhagic transformation but increases risk of secondary stroke in this time frame. Our aim was to compare early anticoagulation with apixaban in AF patients with stroke or transient ischemic attack (TIA) versus warfarin administration at later intervals.

Methods:
AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) was an open-label, randomized controlled trial comparing the safety of early use of apixaban at day 0 to 3 for TIA, day 3 to 5 for small-sized AIS (<1.5 cm), and day 7 to 9 for medium-sized AIS (≥1.5 cm, excluding full cortical territory), to warfarin, in a 1:1 ratio at 1 week post-TIA, or 2 weeks post-AIS.

Results:

Although AREST ended prematurely after a national guideline focused update recommended direct oral anticoagulants over warfarin for AF, it revealed that apixaban had statistically similar yet generally numerically lower rates of recurrent strokes/TIA (14.6% versus 19.2%,
P
=0.78), death (4.9% versus 8.5%,
P
=0.68), fatal strokes (2.4% versus 8.5%,
P
=0.37), symptomatic hemorrhages (0% versus 2.1%), and the primary composite outcome of fatal stroke, recurrent ischemic stroke, or TIA (17.1% versus 25.5%,
P
=0.44). One symptomatic intracerebral hemorrhage occurred on warfarin, none on apixaban. Five asymptomatic hemorrhagic transformation occurred in each arm.

Conclusions:
Early initiation of anticoagulation after TIA, small-, or medium-sized AIS from AF does not appear to compromise patient safety. Potential efficacy of early initiation of anticoagulation remains to be determined from larger pivotal trials.

Registration:

URL:
https://www.clinicaltrials.gov/
; Unique identifier: NCT02283294.
Pregnancy Risk Factors as Predictors of Offspring Cerebrovascular Disease
Authors: Kivelä Milja , Rissanen Ina , Kajantie Eero , Ijäs Hilkka , Rusanen Harri , Miettunen Jouko , Paananen Markus 
Published: February 2021

Background and Purpose:
For prevention of cerebrovascular diseases, it is important to understand the risk factors occurring early in life. The aim was to investigate the relationship of maternal and offspring anthropometrics and pregnancy complications with offspring’s risk of ischemic and hemorrhagic stroke and transient ischemic attack in adulthood.

Methods:
Within the population-based prospective Northern Finland Birth Cohort 1966, 11 991 persons were followed from early pregnancy to 52 years of age. Information on pregnancy and birth complications were collected starting between 24th and 28th gestational week and at birth. Ischemic and hemorrhagic strokes of the offspring were identified from national registers in Finland. Cox proportional hazard models were used to estimate the association of pregnancy and birth complications with incidence of cerebrovascular disease in the offspring, with adjustments for sex, family socioeconomic status, mother’s age, and smoking during pregnancy.

Results:
During 568 821 person-years of follow-up, 453 (3.8%) of the offspring had a stroke or transient ischemic attack. Small and large gestational weight gain among normal weight mothers were associated with increased ischemic stroke risk in offspring (adjusted hazard ratio [aHR], 1.93 [95% CI, 1.28–2.90] and aHR, 1.54 [95% CI, 1.02–2.31], respectively). Small birth weight for gestational age and small ponderal index were associated with increased risk for ischemic stroke (aHR, 1.95 [CI, 1.21–3.13] and aHR, 1.36 [CI, 1.04–1.77], respectively). Threatening miscarriage was also associated with increased risk of any stroke (aHR, 1.64 [CI 1.14–2.37]). Maternal smoking, hypertension, or birth complications were not associated with increased risk of cerebrovascular disease in the offspring.

Conclusions:
The results of this study suggest that disturbances in maternal and fetal growth during pregnancy may predispose offspring to developing cerebrovascular diseases in adulthood.
Hospitalizations for Stroke in France During the COVID-19 Pandemic Before, During, and After the National Lockdown
Authors: Mariet Anne-Sophie , Giroud Maurice , Benzenine Eric , Cottenet Jonathan , Roussot Adrien , Aho-Glélé Ludwig Serge , Tubert-Bitter Pascale , Béjot Yannick , Quantin Catherine 
Published: February 2021

Background and Purpose:
In France, the entire population was put under a total lockdown from March 17 to May 11, 2020 during the peak of the coronavirus disease 2019 (COVID-19) pandemic. Whether the lockdown had consequences on the management of medical emergencies such as stroke and transient ischemic attack (TIA) has yet to be fully evaluated. This article describes hospitalization rates for acute stroke in 2 French regions that experienced contrasting rates of COVID-19 infection, before, during, and after the nationwide lockdown (January to June 2020).

Methods:
All patients admitted for acute stroke/TIA into all public and private hospitals of the 2 study regions were included. Data were retrieved from the National Hospitalization Database (PMSI). In the most affected region (Grand-Est), the hospitalization rates observed in April 2020 were compared with the rates in the same period in the least affected region (Occitanie) and in the 3 prior years (2017–2019).

Results:
There was a significant decline in hospitalization rates for stroke/TIA within the region most affected by COVID-19 during the month of April 2020 compared with previous years, while no significant change was seen in the least affected region. After lockdown, we observed a fast rebound in the rate of hospitalization for stroke/TIA in the most affected region, contrasting with a slower rebound in the least affected region. In both regions, patients with COVID-19 stroke more frequently had ischemic stroke, a nonsignificant greater prevalence of diabetes, they were less frequently admitted to stroke units, and mortality was higher than in patients without COVID-19.

Conclusions:
Our results demonstrates a significant drop in stroke/TIA hospitalizations and a fast recovery after the end of the French lockdown in the most affected region, while the least affected region saw a nonsignificant drop in stroke/TIA hospitalizations and a slow recovery. These results and recommendations could be used by the health authorities to prepare for future challenges.
From the IJssel Valley to Paris and Rome via Montserrat
Authors: Maryks Robert A. 
Published: February 2021

Abstract
This essay aims to analyze the hitherto neglected (or deliberately avoided?) link between De spiritualibus ascentionibus (On spiritual ascents) by Zerbolt of Zutphen (1367–1398) and the Spiritual Exercises of Ignatius of Loyola (c. 1491–1556). Indeed, there is a more direct relationship between these two texts than between Ignatius’s Spiritual Exercises and the Exercitatorio spiritual by Abbot García Jiménez de Cisneros (1455–1510) and the Imitatio Christi (Imitation of Christ) by Thomas à Kempis (c. 1380–1441), which has received much more attention in the existing literature. A careful synoptic reading of these works reveals not only an intriguing congruence between Zerbolt and Loyola in terms of the scope and definition of their works; the general structure and vocabulary; humanistic soteriology and optimistic anthropology of human will; the role of introspection in reforming inordinate affections and affective devotion; the role of examen of conscience (both daily and general); frequent sacramental confession and Communion; the role of spiritual guide; the use of the five senses and composition of place as meditative techniques and importance of methodical mental prayer; and the centrality of imitation of Christ’s humanity, but also direct textual reciprocity. Zerbolt’s Spiritual Ascents appears to be a blueprint for Loyola’s Exercises.
Dispersion of Smoke Plumes over South America
Authors: Jury Mark R. , Gaviria Pabón América R. 
Published: February 2021

AbstractSatellite and reanalysis products are used to study the atmospheric environment, aerosols, and trace gases in smoke plumes over South America in the period 2000–18. Climatic conditions and fire density maps provide context to link biomass burning across the southern Amazon region (5°–15°S, 50°–70°W) to thick near-surface plumes of trace gases and fine aerosols. Intraseasonal weather patterns that underpin greater fire emissions in the dry season (July–October) are exacerbated by high pressure over a cool eastern Pacific Ocean, for example in September 2007. Smoke-plume dispersion simulated with HYSPLIT reveals a slowing of westward transport between sources in eastern Brazil and the Andes Mountains. During cases of thick smoke plumes over southern Amazon, an upper ridge and sinking motions confine trace gases and fine aerosols below 4 km. Long-term warming, which tends to coincide with the zone of biomass burning, is +0.03°C yr−1 in the air and +0.1°C yr−1 at the land surface. Our study suggests that weather conditions promoting fire emissions also tend to limit dispersion.
A Spatiotemporal Lightning Risk Assessment Using Lightning Mapping Data
Authors: Murphy Kelley M. , Bruning Eric C. , Schultz Christopher J. , Vanos Jennifer K. 
Published: February 2021

AbstractA lightning risk assessment for application to human safety was created and applied in 10 west Texas locations from 2 May 2016 to 30 September 2016. The method combined spatial lightning mapping data, probabilistic risk calculation adapted from the International Electrotechnical Commission Standard 62305-2, and weighted average interpolation to produce risk magnitudes that were compared with tolerability thresholds to issue lightning warnings. These warnings were compared with warnings created for the same dataset using a more standard lightning safety approach that was based on National Lightning Detection Network (NLDN) total lightning within 5 n mi (1 n mi = 1.852 km) of each location. Four variations of the calculation as well as different units of risk were tested to find the optimal configuration to calculate risk to an isolated human outdoors. The best-performing risk configuration using risk (10 min)−1 or larger produced the most comparable results to the standard method, such as number of failures, average warning duration, and total time under warnings. This risk configuration produced fewer failures than the standard method but longer total time under warnings and higher false alarm ratios. Median lead times associated with the risk configuration were longer than the standard method for all units considered, whereas median down times were shorter for risk (10 min)−1 and risk (15 min)−1. Overall, the risk method provides a baseline framework to quantify the changing lightning hazard on the storm scale and could be a useful tool to aid in lightning decision support scenarios.