bluuebunny/crossref_metadata_2025_split huggingface dataset:
Losartan and Vitamin D Inhibit Colonic Tumor Development in a Conditional Apc-Deleted Mouse Model of Sporadic Colon Cancer
Authors: Dougherty Urszula , Mustafi Reba , Haider Haider I. , Khalil Abdurahman , Souris Jeffrey S. , Joseph Loren , Hart John , Konda Vani J. , Zhang Wei , Pekow Joel , Li Yan Chun , Bissonnette Marc 
Published: May 2019

Abstract
Colorectal cancer is a leading cause of cancer deaths. The renin-angiotensin system (RAS) is upregulated in colorectal cancer, and epidemiologic studies suggest RAS inhibitors reduce cancer risk. Because vitamin D (VD) receptor negatively regulates renin, we examined anticancer efficacy of VD and losartan (L), an angiotensin receptor blocker. Control Apc+/LoxP mice and tumor-forming Apc+/LoxP Cdx2P-Cre mice were randomized to unsupplemented Western diet (UN), or diets supplemented with VD, L, or VD+L, the latter to assess additive or synergistic effects. At 6 months, mice were killed. Plasma Ca2+, 25(OH)D3, 1α, 25(OH)2D3, renin, and angiotensin II (Ang II) were quantified. Colonic transcripts were assessed by qPCR and proteins by immunostaining and blotting. Cancer incidence and tumor burden were significantly lower in Cre+ VD and Cre+ L, but not in the Cre+ VD+L group. In Apc+/LoxP mice, VD increased plasma 1,25(OH)2D3 and colonic VDR. In Apc+/LoxP-Cdx2P-Cre mice, plasma renin and Ang II, and colonic tumor AT1, AT2, and Cyp27B1 were increased and VDR downregulated. L increased, whereas VD decreased plasma renin and Ang II in Cre+ mice. VD or L inhibited tumor development, while exerting differential effects on plasma VD metabolites and RAS components. We speculate that AT1 is critical for tumor development, whereas RAS suppression plays a key role in VD chemoprevention. When combined with L, VD no longer increases active VD and colonic VDR in Cre- mice nor suppresses renin and Ang II in Cre+ mice, likely contributing to lack of chemopreventive efficacy of the combination.
Hypoxia-Induced VISTA Promotes the Suppressive Function of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment
Authors: Deng Jie , Li Jiannan , Sarde Aurelien , Lines J. Louise , Lee Yu-Chi , Qian David C. , Pechenick Dov A. , Manivanh Richard , Le Mercier Isabelle , Lowrey Christopher H. , Varn Frederick S. , Cheng Chao , Leib David A. , Noelle Randolph J. , Mabaera Rodwell 
Published: May 2019

Abstract
Tumor hypoxia is a negative prognostic factor that is implicated in oncogenic signal activation, immune escape, and resistance to treatment. Identifying the mechanistic role of hypoxia in immune escape and resistance to immune-checkpoint inhibitors may aid the identification of therapeutic targets. We and others have shown that V-domain Ig suppressor of T-cell activation (VISTA), a negative checkpoint regulator in the B7 family, is highly expressed in the tumor microenvironment in tumor models and primary human cancers. In this study, we show that VISTA and HIF1α activity are correlated in a cohort of colorectal cancer patients. High VISTA expression was associated with worse overall survival. We used the CT26 colon cancer model to investigate the regulation of VISTA by hypoxia. Compared with less hypoxic tumor regions or draining lymph nodes, regions of profound hypoxia in the tumor microenvironment were associated with increased VISTA expression on tumor-infiltrating myeloid-derived suppressor cells (MDSC). Using chromatin immunoprecipitation and genetic silencing, we show that hypoxia-inducible factor (HIF)-1α binding to a conserved hypoxia response element in the VISTA promoter upregulated VISTA on myeloid cells. Further, antibody targeting or genetic ablation of VISTA under hypoxia relieved MDSC-mediated T-cell suppression, revealing VISTA as a mediator of MDSC function. Collectively, these data suggest that targeting VISTA may mitigate the deleterious effects of hypoxia on antitumor immunity.
Use of Medicare Claims to Identify Adverse Clinical Outcomes After Mitral Valve Repair
Authors: Lowenstern Angela , Lippmann Steven J. , Brennan J. Matthew , Wang Tracy Y. , Curtis Lesley H. , Feldman Ted , Glower Donald D. , Hammill Bradley G. , Vemulapalli Sreekanth 
Published: May 2019

Background:
Clinical event committees are commonly employed for event validation in clinical studies, but little is known about the comparative performance of administrative claims data versus clinician-triggered event adjudication for ascertainment of adverse events in structural heart disease studies.

Methods and Results:
Medicare claims were linked to 418 patients >65 years of age who underwent transcatheter mitral valve repair (MitraClip) for severe mitral regurgitation from 2007 to 2013 as part of the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study II) High-Risk Registry or the REALISM (Real World Expanded Multicenter Study of the MitraClip System) Continued-Access Registry. Each registry adjudicated mortality, heart failure hospitalization, renal failure, ventilation, and bleeding/transfusion within 1 year. Concordance of claims-based outcomes with events was assessed in 3 ways: 1-year occurrence, cumulative incidence, and synchrony of first events. For event occurrence, positive predictive value (PPV) of claims versus adjudication was the highest for mortality (PPV=97%) and heart failure hospitalization (PPV=69%) but lower for bleeding (PPV=40%) and renal failure (PPV=19%). Whereas claims-based cumulative incidence for mortality, heart failure hospitalization, and renal failure were consistent with clinician-triggered adjudication, incidence curves for bleeding events and ventilation diverged, with claims identifying a greater number of events. When events were detected by both methods, however, over 75% of event dates matched exactly. Mitral valve reinterventions were identified through claims with perfect sensitivity and specificity relative to physician adjudication.

Conclusions:
Ascertainment of mortality, heart failure hospitalization, and renal failure was highly concordant between physician adjudication and administrative claims. Further work is necessary to determine the role of administrative claims in event ascertainment in both prospective and retrospective studies of structural heart disease.
Circulating Selenium Concentration Is Inversely Associated With the Prevalence of Stroke: Results From the Canadian Health Measures Survey and the National Health and Nutrition Examination Survey
Authors: Hu Xue Feng , Stranges Saverio , Chan Laurie H. M. 
Published: May 2019

Background
Observational studies have suggested that selenium (Se) may have beneficial effects against certain cardiovascular outcomes, with a possible U‐shaped association. We assessed the hypothesis that blood Se concentration might be inversely associated with the prevalence of stroke and the relationship would be nonlinear.

Methods and Results

Data collected from adult participants (aged ≥20 years) in the Canadian Health Measures Survey (
CHMS
2007–2011, n=7065) and the
US
National Health and Nutrition Examination Survey (
NHANES
2011–2012, n=5030) were analyzed. A total of 82 (1.16%) and 202 (4.02%) stroke cases were identified in
CHMS
and
NHANES
. Respondents with stroke had lower Se levels than those without stroke, with a mean difference of 16 μg/L and 12 μg/L for
CHMS
and
NHANES
, respectively. Respondents with high blood Se concentration (tertile 3) had a lower prevalence of stroke compared with those with low Se concentration (tertile 1). The adjusted odds ratios were 0.38 (95%
CI
: 0.15, 0.92) and 0.57 (95%
CI
: 0.31, 1.03) for
CHMS
and
NHANES
, respectively. A continuous decreasing trend of stroke with whole blood selenium was observed in
CHMS
, whereas the curve plateaued starting at 190 μg/L for
NHANES
, based on the cubic restricted spline regression. Sensitivity analysis using the serum and urinary Se concentrations demonstrates that our results were consistent across different selenium biomarkers.

Conclusions

We observed inverse cross‐sectional associations between whole blood Se and the prevalence of stroke in representative samples of the Canadian and the
US
population.
Overlap in the Genetic Architecture of Stroke Risk, Early Neurological Changes, and Cardiovascular Risk Factors
Authors: Ibanez Laura , Heitsch Laura , Dube Umber , Farias Fabiana H.G. , Budde John , Bergmann Kristy , Davenport Rich , Bradley Joseph , Carrera Caty , Kinnunen Janne , Sallinen Hanne , Strbian Daniel , Slowik Agnieszka , Fernandez-Cadenas Israel , Montaner Joan , Lee Jin-Moo , Cruchaga Carlos ,   on behalf of the International Stroke Genetics Consortium and the MEGASTROKE Consortium*
Published: May 2019

Background and Purpose—
The genetic relationships between stroke risk, stroke severity, and early neurological changes are complex and not completely understood. Genetic studies have identified 32 all stroke risk loci. Polygenic risk scores can be used to compare the genetic architecture of related traits. In this study, we compare the genetic architecture of stroke risk, stroke severity, and early neurological changes with that of 2 stroke risk factors: type 2 diabetes mellitus (T2DM) and hypertension.

Methods—

We assessed the degree of overlap in the genetic architecture of stroke risk, T2DM, hypertension, and 2 acute stroke phenotypes based on the National Institutes of Health Stroke Scale (NIHSS), which ranges from 0 for no stroke symptoms to 21 to 42 for a severe stroke: baseline (within 6 hours after onset) and change in NIHSS (ΔNIHSS=NIHSS at baseline−NIHSS at 24 hours). This was done by (1) single-nucleotide polymorphism by single-nucleotide polymorphism comparison, (2) weighted polygenic risk scores with sentinel variants, and (3) whole-genome polygenic risk scores using multiple
P
thresholds.

Results—

We found evidence of genetic architecture overlap between stroke risk and T2DM (
P
=2.53×10
−
169
), hypertension (
P
=3.93×10
−
04
), and baseline NIHSS (
P
=0.03). However, there was no evidence of overlap between ΔNIHSS and stroke risk, T2DM, or hypertension.

Conclusions—
The genetic architecture of stroke risk is correlated with that of T2DM, hypertension, and initial stroke severity (NIHSS within 6 hours of stroke onset). However, the genetic architecture of early neurological change after stroke (ΔNIHSS) is not correlated with that of ischemic stroke risk, T2DM, or hypertension. Thus, stroke risk and early neurological change after stroke have distinct genetic architectures.
Location of Neutrophils in Different Compartments of the Damaged Mouse Brain After Severe Ischemia/Reperfusion
Authors: Otxoa-de-Amezaga Amaia , Gallizioli Mattia , Pedragosa Jordi , Justicia Carles , Miró-Mur Francesc , Salas-Perdomo Angelica , Díaz-Marugan Laura , Gunzer Matthias , Planas Anna M. 
Published: May 2019

Background and Purpose—
Ischemia attracts neutrophils to the injured brain. However, neutrophil location and access to the damaged brain tissue is not yet entirely understood. We aimed to investigate neutrophil location in a mouse model of cerebral ischemia/reperfusion.

Methods—

Adult male C57BL/6 mice (n=52) received 45-minute intraluminal middle cerebral artery occlusion followed by 14, 24, 48, or 96 hours of reperfusion. Sham-operated mice (n=9) were subjected to the entire surgical procedure. We used wild-type mice and Catchup
IVM
mice expressing a red fluorescent protein in neutrophils. In addition, fluorescent neutrophils obtained from reporter DsRed (discosoma red fluorescent protein) mice were transferred intravenously to wild-type mice after ischemia. Mice received transcardial paraformaldehyde perfusion, the brain was cryoprotected, frozen, and cryostat sections were studied by immunofluorescence and confocal microscopy.

Results—
Ischemia induced a time-dependent increase in brain neutrophil numbers versus sham operation. We detected neutrophils in the leptomeninges, ventricles, capillary lumen, perivascular spaces, and parenchyma within the infarcted core. Most ischemic mice showed neutrophils in the leptomeninges and perivascular spaces, whereas the presence and number of neutrophils in the parenchyma was variable among ischemic mice. During the first 24 hours, only a few mice showed parenchymal neutrophils, but the frequency of mice showing neutrophils in the parenchyma and neutrophil numbers increased at 48 and 96 hours. We also detected signs of basement membrane disruption and hints of occasional neutrophil degranulation and formation of neutrophil extracellular traps.

Conclusions—
After ischemia/reperfusion, neutrophils accumulate in the leptomeninges and perivascular spaces, and eventually can reach the infarcted brain parenchyma.
Disparities and Temporal Trends in the Use of Anticoagulation in Patients With Ischemic Stroke and Atrial Fibrillation
Authors: Sur Nicole B. , Wang Kefeng , Di Tullio Marco R. , Gutierrez Carolina M. , Dong Chuanhui , Koch Sebastian , Gardener Hannah , García-Rivera Enid J. , Zevallos Juan Carlos , Burgin W. Scott , Rose David Z. , Goldberger Jeffrey J. , Romano Jose G. , Sacco Ralph L. , Rundek Tatjana 
Published: May 2019

Background and Purpose—
Ischemic stroke (IS) secondary to atrial fibrillation (AF) is largely preventable with the use of anticoagulation. We sought to identify race-ethnicity and sex disparities with the use of direct oral anticoagulants (DOACs), aspirin, and warfarin in IS patients with AF and to identify temporal trends in the utilization of these medications.

Methods—
The FLiPER-AF Stroke Study (Florida Puerto Rico Atrial Fibrillation) included 24 040 IS cases enrolled in the Florida-Puerto Rico Collaboration to Reduce Stroke Registry from 2010 to 2016. Multivariable logistic regression models were performed to evaluate the effect of race-ethnicity and sex on utilization of DOACs, aspirin, and warfarin for stroke prevention in AF after adjustment for sociodemographic, hospital, and clinical factors.

Results—
Among 24 040 IS cases, 54% were women and 10% black, 12% FL-Hispanics, 4% PR-Hispanic, and 74% whites. From 2010 to 2016, DOAC use increased from 0% to 36%, warfarin use decreased from 51% to 17%, and aspirin use remained relatively stable (42%–40%). After adjustment, blacks had higher odds of warfarin (odds ratio, 1.22; 95% CI, 1.07–1.40) prescription at discharge compared with whites. Men had higher rates of aspirin (42.1% versus 38.8%), warfarin (33.6% versus 28.9%), and DOAC (21.3% versus 19.3%) use compared with women. After adjustment, women had lower odds of being discharged on aspirin (odds ratio, 0.92; 95% CI, 0.86–0.98) or warfarin (odds ratio, 0.91; 95% CI, 0.84–0.99). There was no sex difference in use of DOACs.

Conclusions—
Our study confirmed the increasing use of DOACs, downtrending use of warfarin, whereas aspirin use remained similar over the years. There are sex and race-ethnicity disparities in anticoagulation use in IS patients with AF. It is critical to understand underlying drivers of these disparities to develop better practice strategies for stroke prevention in patients with AF.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT03627806.
SCENT Trial
Authors: Meyers Philip M. , Coon Alexander L. , Kan Peter T. , Wakhloo Ajay K. , Hanel Ricardo A. 
Published: May 2019

Background and Purpose—
To evaluate the safety and effectiveness of the Surpass Flow Diverter (Surpass; Stryker Neurovascular, Fremont, CA) in the treatment of large or giant wide-neck intracranial aneurysms at one year, we hypothesize that treatment with Surpass meets or improves on historical safety and efficacy end points.

Methods—
SCENT trial (Surpass Intracranial Aneurysm Embolization System Pivotal Trial to Treat Large or Giant Wide Neck Aneurysms) is a multicenter, prospective, single-arm, nonrandomized, interventional trial of the Surpass Flow Diverter for uncoilable or previously treated but failed aneurysms of the intracranial internal carotid artery extending from the petrous segment to the carotid terminus at its bifurcation into anterior and middle cerebral arteries. For enrollment in SCENT, target aneurysms had to be wide-neck (≥4 mm) and large or giant size (≥10 mm). Study results are compared with performance goals derived from a thorough review of the medical literature. The primary effectiveness end point included 3 components: complete aneurysm occlusion, absence of significant parent artery stenosis (≥50%), and no retreatment at 12 months. The primary safety end point was major ipsilateral stroke (increase in National Institutes of Health Stroke Scale score of ≥4) or neurological death within 12 months.

Results—
At 26 medical centers, 180 patients with 180 target aneurysms were enrolled in the modified intention-to-treat cohort. Per angiographic core lab assessment, there were 15 (8.3%) fusiform, 164 (91.1%) saccular aneurysms, and 1 (0.6%) blister aneurysm. Mean aneurysm size was 12.0 mm. Thirteen (7.4%) aneurysms were giant (≥25 mm). Fifty-eight (32.2%) aneurysms were located in the supraclinoid and distal (including posterior communicating artery) segments of the internal carotid artery. Mean procedure duration was 53.6 minutes. The device was successfully implanted in 97.8% of patients with a mean of 1.1 devices per patient. SCENT met both primary safety and effectiveness end points: 12-month primary effectiveness rate was 62.8% [(113/180); 95% CI, 55.3–69.9] and 12-month major ipsilateral stroke or neurological death rate was 8.3% [(15/180); 95% CI, 4.7–13.4].

Conclusions—
Surpass provides safe and effective flow diversion of large or giant, wide-neck, intracranial internal carotid artery aneurysms.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01716117.
Thrombectomy Outcomes of Intracranial Atherosclerosis-Related Occlusions
Authors: Tsang Anderson Chun On , Orru Emanuele , Klostranec Jesse M. , Yang I-Hsiao , Lau Kui Kai , Tsang Frederick Chun Pong , Lui Wai Man , Pereira Vitor Mendes , Krings Timo 
Published: May 2019

Background and Purpose—
Intracranial atherosclerosis (ICAS) is an important cause of large vessel occlusion and poses unique challenges for emergent endovascular thrombectomy. The risk factor profile and therapeutic outcomes of patients with ICAS-related occlusions (ICAS-O) are unclear. We performed a systematic review and meta-analysis of studies reporting the clinical features and thrombectomy outcomes of large vessel occlusion stroke secondary to underlying ICAS (ICAS-O) versus those of other causes (non–ICAS-O).

Methods—
A literature search on thrombectomy for ICAS-O was performed. Random-effect meta-analysis was used to analyze the prevalence of stroke risk factors and outcomes of thrombectomy between ICAS-O and non–ICAS-O groups.

Results—
A total of 1967 patients (496 ICAS-O and 1471 non–ICAS-O) were included. The ICAS-O group had significantly higher prevalence of hypertension (odds ratio [OR] 1.46; 95% CI, 1.10–1.93), diabetes mellitus (OR, 1.68; 95% CI, 1.29–2.20), dyslipidemia (OR, 1.94; 95% CI, 1.04–3.62), smoking history (OR, 2.11; 95% CI, 1.40–3.17) but less atrial fibrillation (OR, 0.20; 95% CI, 0.13–0.31) than the non–ICAS-O group. About thrombectomy outcomes, ICAS-O had higher intraprocedural reocclusion rate (OR, 23.7; 95% CI, 6.96–80.7), need for rescue balloon angioplasty (OR, 9.49; 95% CI, 4.11–21.9), rescue intracranial stenting (OR, 14.9; 95% CI, 7.64–29.2), and longer puncture-to-reperfusion time (80.8 versus 55.5 minutes, mean difference 21.3; 95% CI, 11.3–31.3). There was no statistical difference in the rate of final recanalization (modified Thrombolysis in Cerebral Infarction score of 2b/3; OR, 0.67; 95% CI, 0.36–1.27), symptomatic intracerebral hemorrhage (OR, 0.79; 95% CI, 0.50–1.24), good functional outcome (modified Rankin Scale score of 0–2; OR, 1.16; 95% CI, 0.85–1.58), and mortality (OR, 0.94; 95% CI, 0.64–1.39) between ICAS-O and non–ICAS-O.

Conclusions—
Patients with ICAS-O display a unique risk factor profile and technical challenges for endovascular reperfusion therapy. Intraprocedural reocclusion occurs in one-third of patients with ICAS-O. Intraarterial glycoprotein IIb/IIIa inhibitors infusion, balloon angioplasty, and intracranial stenting may be viable rescue treatment to achieve revascularization, resulting in comparable outcomes to non–ICAS-O.
Temporal Trends in Ischemic Stroke Incidence in Younger Adults in the Framingham Study
Authors: Aparicio Hugo J. , Himali Jayandra J. , Satizabal Claudia L. , Pase Matthew P. , Romero Jose R. , Kase Carlos S. , Beiser Alexa S. , Seshadri Sudha 
Published: May 2019

Background and Purpose—
Stroke at midlife has a disproportionately large impact on disability-adjusted life-years lost. Ischemic stroke incidence may be increasing at this age. We investigated long-term trends in ischemic stroke incidence and changes in stroke risk factors in a community sample stratified by stroke onset at middle and older age.

Methods—
In the Framingham Study, surveillance for incident stroke is ongoing since 1948. We examined age-adjusted and sex-adjusted 10-year incidence of ischemic stroke using Cox models in persons aged 35 to 54 and ≥55 years at start of follow-up. Tests for linear trend were performed over 4 epochs, controlling for the distance in time between intervals. Further, we calculated the mean 10-year risk of stroke at each epoch and for both age groups, based on vascular risk factors from the Framingham Stroke Risk Profile.

Results—

There were 153, 197, 176, and 165 incident ischemic strokes within each epoch beginning in 1962 (n=3966), 1971 (n=5779), 1987 (n=5133), and 1998 (n=6964). Most ischemic strokes at midlife (n=71) were because of atherosclerotic brain infarction (n=50) or cardioembolism (n=19). Using the risk in the 1962 epoch as the reference, the risk of ischemic stroke at midlife did not significantly decline (hazard ratio, 0.87; 95% CI, 0.74–1.02;
P
trend =0.09). Incidence of ischemic stroke declined in the older group (hazard ratio, 0.82; 95% CI, 0.77–0.88;
P
trend <0.001). Between epochs 1 and 4, the average 10-year risk of stroke, as estimated by the Framingham Stroke Risk Profile, declined by 0.7% at midlife and 1.1% at older age.

Conclusions—
Long-term rates of ischemic stroke declined in our community sample; the decline was greater in older as compared with younger adults. Early prevention, focused on modification of cardiovascular risk factors, is important to see sustained declines in stroke incidence and mortality at midlife.
Claimed and Unclaimed Experience: Problematic Readings of Trauma in the Hebrew Bible
Authors: Janzen David 
Published: May 2019

Abstract
The understanding of trauma in sociology as the group’s creation of meaning for horrific events has been highly influential in the study of the Hebrew Bible. This sociological approach is very different than that of literary criticism, where trauma is understood through the lens of psychoanalytical analysis as that which has not been fully experienced by victims and is not truly known by them, as “unclaimed experience,” in other words. The sociological understanding of trauma has helped scholars understand potential social benefits of biblical texts, but scholarship often fails to clearly distinguish this approach from that of psychoanalysis and literary criticism, and this has led to problematic claims that texts which create meaning for traumatic events will prove to be therapeutic for individual trauma sufferers. The use of texts to create meaning and explanation actually forces trauma victims to repress the speech about their trauma that they need to engage in therapy.