bluuebunny/crossref_metadata_2025_split huggingface dataset:
Machine-Learning Prediction of Tumor Antigen Immunogenicity in the Selection of Therapeutic Epitopes
Authors: Smith Christof C. , Chai Shengjie , Washington Amber R. , Lee Samuel J. , Landoni Elisa , Field Kevin , Garness Jason , Bixby Lisa M. , Selitsky Sara R. , Parker Joel S. , Savoldo Barbara , Serody Jonathan S. , Vincent Benjamin G. 
Published: September 2019

Abstract
Current tumor neoantigen calling algorithms primarily rely on epitope/major histocompatibility complex (MHC) binding affinity predictions to rank and select for potential epitope targets. These algorithms do not predict for epitope immunogenicity using approaches modeled from tumor-specific antigen data. Here, we describe peptide-intrinsic biochemical features associated with neoantigen and minor histocompatibility mismatch antigen immunogenicity and present a gradient boosting algorithm for predicting tumor antigen immunogenicity. This algorithm was validated in two murine tumor models and demonstrated the capacity to select for therapeutically active antigens. Immune correlates of neoantigen immunogenicity were studied in a pan-cancer data set from The Cancer Genome Atlas and demonstrated an association between expression of immunogenic neoantigens and immunity in colon and lung adenocarcinomas. Lastly, we present evidence for expression of an out-of-frame neoantigen that was capable of driving antitumor cytotoxic T-cell responses. With the growing clinical importance of tumor vaccine therapies, our approach may allow for better selection of therapeutically relevant tumor-specific antigens, including nonclassic out-of-frame antigens capable of driving antitumor immunity.
Elevated Plasma Ceramides Are Associated With Higher White Matter Hyperintensity Volume—Brief Report
Authors: Mielke Michelle M. , Syrjanen Jeremy A. , Bui Hai H. , Petersen Ronald C. , Knopman David S. , Jack Clifford R. , Graff-Radford Jonathan , Vemuri Prashanthi 
Published: September 2019

Objective:
Sphingolipids, including S1P (sphingosine-1-phosphate) and ceramides, have been associated with vascular tone, blood pressure regulation, cardiovascular outcomes, and mortality. However, the relationship between plasma sphingolipids and cerebrovascular disease has not been examined. We aimed to assess the cross-sectional association between plasma sphingolipids and white matter hyperintensity (WMH) volume, which is a marker of cerebrovascular disease.

Approach and Results:
We included 588 participants (302 men and 286 women), aged 60 to 93, enrolled in the population-based Mayo Clinic Study of Aging who had MRI and plasma sphingolipids at the same study visit. Fasting plasma was obtained, and ceramides and S1P were assayed using liquid chromatography-electrospray ionization tandem mass spectrometry. Fluid-attenuated inversion recovery was used to measure WMH volume, defined as percent total intracranial volume. We used linear regression to cross-sectionally examine the relationships between plasma sphingolipids and WMH; both were log-transformed. In multivariable analyses adjusting for age, sex, and hypertension, higher levels of ceramide C16:0 (b [95% CI]=0.24 [0.02–0.45]) and the ceramide ratios C16:0_24:0 (b [95% CI]=0.30 [0.12–0.48]) and C24:1_24:0 (b [95% CI]=0.24 [0.07–0.41]) were associated with a higher WMH volume. A higher ceramide score was also associated with higher WMH volume (b [95% CI]=0.03 (0.01–0.04]). We did not observe any association between S1P and WMH volume.

Conclusions:
Higher plasma ceramide C16:0 and 2 specific ceramide ratios (C16:0_24:0 and C24:1_24:0) are associated with greater WMH volumes, independent of hypertension, suggesting their utility for measurement of cerebrovascular disease.
Treatments and Mortality Trends in Cases With and Without Dialysis Who Have an Acute Myocardial Infarction
Authors: Szummer Karolina , Lindhagen Lars , Evans Marie , Spaak Jonas , Koul Sasha , Åkerblom Axel , Carrero Juan Jesus , Jernberg Tomas 
Published: September 2019

Background:
Patients on dialysis who have an acute myocardial infarction (AMI) have an exceedingly poor prognosis, but it is unknown to what extent guideline-recommended interventions and treatments are used and to which benefit. We aimed to assess temporal changes in the use of treatments and survival rates in dialysis patients with an AMI.

Methods and Results:

All consecutive AMI cases from 1996 to 2013 enrolled in the SWEDEHEART registry (Swedish Web–System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) were included. The Swedish Renal Registry identified all chronic dialysis cases. Multivariable adjusted standardized 1-year mortality was estimated. An age-sex-calendar year–matched dialysis background population from the Swedish Renal Registry was used to obtain a standardized incidence ratio. All analyses were performed in 2-year blocks, where each individual could be included several times but in different time blocks; hence the term AMI cases and not patients is used. Of 289 699 cases with AMI, 1398 (0.5%) were on dialysis (73.6% hemodialysis; 26.4% peritoneal dialysis). Among dialysis cases, 29.4% were women, and 21.0% had ST-segment–elevation myocardial infarction. Through 1996 to 2013, dialysis cases had similar age (median, 70 years [interquartile range, 62–77];
P
for trend, 0.14), but the proportion with diabetes mellitus increased (36.0%–55.3%;
P
for trend, 0.005). Dialysis cases admitted with AMI were treated more invasively and received more discharge medications in the later years. From 1995 to 2013, in-hospital and 1-year mortality decreased from 25.4% to 9.4% and from 59.6% to 41.2%, respectively. The standardized in-hospital and 1-year mortality decreased from 25.7% to 9.4% and from 54.6% to 41.2%. Yet, compared with the matched dialysis population, the odds of death remained as high in 2012/2013 as in 1996/1997 (odds ratio, 2.04; 95% CI, 1.62–2.58 and odds ratio, 1.99; 95% CI, 1.52–2.60, respectively;
P
for trend, 0.34).

Conclusions:
Over the last 18 years, more patients on dialysis with AMI have been treated with evidence-based therapies. Overall, dialysis cases with AMI have an improved in-hospital and 1-year survival in the more recent years compared with earlier years. However, this appears largely to be because of improved survival in the general dialysis population.
Cell-Specific Gene Deletion Reveals the Antithrombotic Function of COX1 and Explains the Vascular COX1/Prostacyclin Paradox
Authors: Mitchell Jane A. , Shala Fisnik , Elghazouli Youssef , Warner Timothy D. , Gaston-Massuet Carles , Crescente Marilena , Armstrong Paul C. , Herschman Harvey R. , Kirkby Nicholas S. 
Published: September 2019

Rationale:

Endothelial cells (ECs) and platelets, which respectively produce antithrombotic prostacyclin and prothrombotic thromboxane A
2
, both express COX1 (cyclooxygenase1). Consequently, there has been no way to delineate any antithrombotic role for COX1-derived prostacyclin from the prothrombotic effects of platelet COX1. By contrast, an antithrombotic role for COX2, which is absent in platelets, is straightforward to demonstrate. This has resulted in an incomplete understanding of the relative importance of COX1 versus COX2 in prostacyclin production and antithrombotic protection in vivo.

Objective:
We sought to identify the role, if any, of COX1-derived prostacyclin in antithrombotic protection in vivo and compare this to the established protective role of COX2.

Methods and Results:

We developed vascular-specific COX1 knockout mice and studied them alongside endothelial-specific COX2 knockout mice. COX1 immunoreactivity and prostacyclin production were primarily associated with the endothelial layer of aortae; freshly isolated aortic ECs released >10-fold more prostacyclin than smooth muscle cells. Moreover, aortic prostacyclin production, the ability of aortic rings to inhibit platelet aggregation and plasma prostacyclin levels were reduced when COX1 was knocked out in ECs but not in smooth muscle cells. When thrombosis was measured in vivo after FeCl
3
carotid artery injury, endothelial COX1 deletion accelerated thrombosis to a similar extent as prostacyclin receptor blockade. However, this effect was lost when COX1 was deleted from both ECs and platelets. Deletion of COX2 from ECs also resulted in a prothrombotic phenotype that was independent of local vascular prostacyclin production.

Conclusions:
These data demonstrate for the first time that, in healthy animals, endothelial COX1 provides an essential antithrombotic tone, which is masked when COX1 activity is lost in both ECs and platelets. These results help us define a new 2-component paradigm wherein thrombotic tone is regulated by both COX1 and COX2 through complementary but mechanistically distinct pathways.
Bleeding and New Cancer Diagnosis in Patients With Atherosclerosis
Authors: Eikelboom John W. , Connolly Stuart J. , Bosch Jacqueline , Shestakovska Olga , Aboyans Victor , Alings Marco , Anand Sonia S. , Avezum Alvaro , Berkowitz Scott D. , Bhatt Deepak L. , Cook-Bruns Nancy , Felix Camilo , Fox Keith A.A. , Hart Robert G. , Maggioni Aldo P. , Moayyedi Paul , O’Donnell Martin , Rydén Lars , Verhamme Peter , Widimsky Petr , Zhu Jun , Yusuf Salim ,   On behalf of the COMPASS Investigators
Published: September 2019

Background:
Patients treated with antithrombotic drugs are at risk of bleeding. Bleeding may be the first manifestation of underlying cancer.

Methods:
We examined new cancers diagnosed in relation to gastrointestinal or genitourinary bleeding among patients enrolled in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) and determined the hazard of new cancer diagnosis after bleeding at these sites.

Results:
Of 27 395 patients enrolled (mean age, 68 years; women, 21%), 2678 (9.8%) experienced any (major or minor) bleeding, 713 (2.6%) experienced major bleeding, and 1084 (4.0%) were diagnosed with cancer during a mean follow-up of 23 months. Among 2678 who experienced bleeding, 257 (9.9%) were subsequently diagnosed with cancer. Gastrointestinal bleeding was associated with a 20-fold higher hazard of new gastrointestinal cancer diagnosis (7.4% versus 0.5%; hazard ratio [HR], 20.6 [95% CI, 15.2–27.8]) and 1.7-fold higher hazard of new nongastrointestinal cancer diagnosis (3.8% versus 3.1%; HR, 1.70 [95% CI, 1.20–2.40]). Genitourinary bleeding was associated with a 32-fold higher hazard of new genitourinary cancer diagnosis (15.8% versus 0.8%; HR, 32.5 [95% CI, 24.7–42.9]), and urinary bleeding was associated with a 98-fold higher hazard of new urinary cancer diagnosis (14.2% versus 0.2%; HR, 98.5; 95% CI, 68.0–142.7). Nongastrointestinal, nongenitourinary bleeding was associated with a 3-fold higher hazard of nongastrointestinal, nongenitourinary cancers (4.4% versus 1.9%; HR, 3.02 [95% CI, 2.32–3.91]).

Conclusions:
In patients with atherosclerosis treated with antithrombotic drugs, any gastrointestinal or genitourinary bleeding was associated with higher rates of new cancer diagnosis. Any gastrointestinal or genitourinary bleeding should prompt investigation for cancers at these sites.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01776424.
Impact of a Multidisciplinary Treatment Pathway for Atrial Fibrillation in the Emergency Department on Hospital Admissions and Length of Stay: Results of a Multi‐Center Study
Authors: Ptaszek Leon M. , Baugh Christopher W. , Lubitz Steven A. , Ruskin Jeremy N. , Ha Grace , Forsch Margaux , DeOliveira Samer A. , Baig Samia , Heist E. Kevin , Wasfy Jason H. , Brown David F. , Biddinger Paul D. , Raja Ali S. , Scirica Benjamin , White Benjamin A. , Mansour Moussa 
Published: September 2019

Background

Variability in the management of atrial fibrillation (
AF
) in the emergency department (
ED
) leads to avoidable hospital admissions and prolonged length of stay (
LOS
). In a retrospective single‐center study, a multidisciplinary
AF
treatment pathway was associated with a reduced hospital admission rate and reduced
LOS
. To assess the applicability of the
AF
pathway across institutions, we conducted a 2‐center study.

Methods and Results

We performed a prospective, 2‐stage study at 2 tertiary care hospitals. During the first stage,
AF
patients in the
ED
received routine care. During the second stage,
AF
patients received care according to the
AF
pathway. The primary study outcome was hospital admission rate. Secondary outcomes included
ED LOS
and inpatient
LOS
. We enrolled 104 consecutive patients in each stage. Patients treated using the
AF
pathway were admitted to the hospital less frequently than patients who received routine care (15% versus 55%;
P
<0.001). For admitted patients, average hospital
LOS
was shorter in the
AF
pathway cohort than in the routine care cohort (64 versus 105 hours, respectively;
P
=0.01). There was no significant difference in the average
ED LOS
between
AF
pathway and routine care cohorts (14 versus 12 hours, respectively;
P
=0.32).

Conclusions

In this prospective 2‐stage, 2‐center study, utilization of a multidisciplinary
AF
treatment pathway resulted in a 3.7‐fold reduction in admission rate and a 1.6‐fold reduction in average hospital
LOS
for admitted patients. Utilization of the
AF
pathway was not associated with a significant change in
ED LOS
.
Renal Resistive Index Is Associated With Inactive Matrix Gla (γ‐Carboxyglutamate) Protein in an Adult Population‐Based Study
Authors: Jaques David A. , Pivin Edward , Pruijm Menno , Ackermann Daniel , Guessous Idris , Ehret Georg , Wei Fang‐Fei , Staessen Jan A. , Pechère‐Bertschi Antoinette , Vermeer Cees , Vogt Bruno , Burnier Michel , Martin Pierre‐Yves , Bochud Murielle , Ponte Belen 
Published: September 2019

Background

Increased renal resistive index (
RRI
) has been associated with target organ damage as well as renal and cardiovascular outcomes. Matrix Gla (γ‐carboxyglutamate) protein (
MGP
) is a strong inhibitor of soft tissue calcification. Its inactive form (dephospho‐uncarboxylated MGP [dp‐uc
MGP
]) has been associated with vascular stiffness, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp‐uc
MGP
were associated with increased
RRI
.

Methods and Results

We recruited participants via a multicenter family‐based cross‐sectional study in Switzerland. Levels of dp‐uc
MGP
were measured in plasma by sandwich
ELISA
.
RRI
was measured by Doppler ultrasound in 3 segmental arteries in both kidneys. We used mixed regression models to assess the relationship between dp‐uc
MGP
and
RRI
. We adjusted for common determinants of
RRI
as well as renal function and cardiovascular risk factors. We included 1006 participants in our analyses: 526 women and 480 men. Mean values were 0.44±0.20 nmol/L for dp‐uc
MGP
and 64±5% for
RRI
. After multivariable adjustment, dp‐uc
MGP
was positively associated with
RRI
(
P
=0.001). In subgroup analysis by age tertiles, this association was not significant in the youngest age group (<38 years;
P
=0.62), whereas it was significant in older age groups (38–55 and >55 years;
P
=0.016 and
P
<0.001, respectively).

Conclusions

Levels of dp‐uc
MGP
are positively and independently associated with
RRI
after adjustment for common determinants of
RRI
, cardiovascular risk factors, and renal function. The stronger association among older adults is probably due, in part, to age‐related arterial stiffness.
RRI
thus seems to reflect the global atherosclerotic burden in a general adult population.
Brain Connectivity Measures Improve Modeling of Functional Outcome After Acute Ischemic Stroke
Authors: Ktena Sofia Ira , Schirmer Markus D. , Etherton Mark R. , Giese Anne-Katrin , Tuozzo Carissa , Mills Brittany B. , Rueckert Daniel , Wu Ona , Rost Natalia S. 
Published: September 2019

Background and Purpose—
The ability to model long-term functional outcomes after acute ischemic stroke represents a major clinical challenge. One approach to potentially improve prediction modeling involves the analysis of connectomics. The field of connectomics represents the brain’s connectivity as a graph, whose topological properties have helped uncover underlying mechanisms of brain function in health and disease. Specifically, we assessed the impact of stroke lesions on rich club organization, a high capacity backbone system of brain function.

Methods—

In a hospital-based cohort of 41 acute ischemic stroke patients, we investigated the effect of acute infarcts on the brain’s prestroke rich club backbone and poststroke functional connectomes with respect to poststroke outcome. Functional connectomes were created using 3 anatomic atlases, and characteristic path-length (
L
) was calculated for each connectome. The number of rich club regions affected were manually determined using each patient’s diffusion weighted image. We investigated differences in
L
with respect to outcome (modified Rankin Scale score; 90 days) and the National Institutes of Health Stroke Scale (NIHSS; early: 2–5 days; late: 90-day follow-up). Furthermore, we assessed the effect of including number of rich club regions and
L
in outcome models, using linear regression and assessing the explained variance (R
2
).

Results—

Of 41 patients (mean age [range]: 70 [45–89] years), 61% were male. Lower
L
was generally associated with better outcome. Including number of rich club regions in the backward selection models of outcome, R
2
increased between 1.3- and 2.6-fold beyond that of traditional markers (age and acute lesion volume) for NIHSS and modified Rankin Scale score.

Conclusions—
In this proof-of-concept study, we showed that information on network topology can be leveraged to improve modeling of poststroke functional outcome. Future studies are warranted to validate this approach in larger prospective studies of outcome prediction in stroke.
Clot-Derived Contaminants in Transplanted Bone Marrow Mononuclear Cells Impair the Therapeutic Effect in Stroke
Authors: Okinaka Yuka , Kikuchi-Taura Akie , Takeuchi Yukiko , Ogawa Yuko , Boltze Johannes , Gul Sheraz , Claussen Carsten , Taguchi Akihiko 
Published: September 2019

Background and Purpose—
The beneficial effects of bone marrow mononuclear cell (BM-MNC) transplantation in preclinical experimental stroke have been reliably demonstrated. However, only overall modest effects in clinical trials were observed. We have investigated and reported a cause of the discrepancy between the preclinical and clinical studies.

Methods—
To investigate the possible cause of low efficacy of BM-MNC transplantation in experimental stroke, we have focused on blood clot formation, which is not uncommon in human bone marrow aspirates. To evaluate the effects of clot-derived contaminants in transplanted BM-MNC on stroke outcome, a murine stroke model was used.

Results—
We show that BM-MNC separated by an automatic cell isolator (Sepax2), which does not have the ability to remove clots, did not attenuate brain atrophy after stroke. In contrast, manually isolated, clot-free BM-MNC exerted therapeutic effects. Clot-derived contaminants were also transplanted intravenously to poststroke mice. We found that the transplanted contaminants were trapped at the peristroke area, which were associated with microglial/macrophage activation.

Conclusions—
Clot-derived contaminants in transplanted BM-MNC nullify therapeutic effects in experimental stroke. This may explain neutral results in clinical trials, especially in those using automated stem cell separators that lack the ability to remove clot-derived contaminants.

Visual Overview—

An online
visual overview
is available for this article.
Narrative Explanations: The Case for Causality
Authors: Gangl Georg 
Published: September 2019

Abstract
In this paper I argue that historiography employs causal narrative explanations just as other historical sciences such as evolutionary biology or paleontology do. There is a logic of explanation common to all these sciences that centers on causal explanation of unique and unrepeatable events. The explanandum of historiography can further be understood as mechanism in the sense developed by Stuart Glennan and others in recent years. However, causal explanation is not the only way historiography relates to the past. Arthur Danto has given us the theoretical tools to differentiate between causal narratives and conceptual colligations, with both playing a pivotal role in historiography even though Danto himself has not expressed that thought clearly.
Test of a Weather-Adaptive Dual-Resolution Hybrid Warn-on-Forecast Analysis and Forecast System for Several Severe Weather Events
Authors: Wang Yunheng , Gao Jidong , Skinner Patrick S. , Knopfmeier Kent , Jones Thomas , Creager Gerry , Heiselman Pamela L. , Wicker Louis J. 
Published: September 2019

Abstract
A real-time, weather adaptive, dual-resolution, hybrid Warn-on-Forecast (WoF) analysis and forecast system using the WRF-ARW forecast model has been developed and implemented. The system includes two components, an ensemble analysis and forecast component, and a deterministic hybrid three-dimensional ensemble–variational (3DEnVAR) analysis and forecast component. The goal of the system is to provide on-demand, ensemble-based, and physically consistent gridded analysis and forecast products to forecasters for making warning decisions. Both components, the WRF-DART system with 36 ensemble members and the hybrid 3DEnVAR system, assimilate radar data, satellite-retrieved cloud water path, and surface observations at 15-min intervals with dual-resolution capability. In the current hybrid configuration, one-way coupling of the two analysis systems is performed: ensemble covariances derived from the WRF-DART system are incorporated into the hybrid 3DEnVAR system with each data assimilation (DA) cycle. This study examines deterministic, 3-h forecasts launched from the hybrid 3DEnVAR analyses every 30 min for three severe weather events in 2017. The performance of the deterministic component is evaluated for four configurations: dual-resolution coupling, single-resolution coupling, forecasts initialized using a cloud analysis for reflectivity assimilation, and forecasts initialized from the WRF-DART ensemble mean. Quantitative and subjective evaluation of composite reflectivity and updraft helicity (UH) swath forecasts for the three events indicate that the dual-resolution strategy without the cloud analysis performs best among the four configurations and provides the most realistic prediction of reflectivity patterns and UH tracks.