bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidemiology of hypertension in Northern Tanzania: a community-based mixed-methods study
Authors: Galson Sophie W , Staton Catherine A , Karia Francis , Kilonzo Kajiru , Lunyera Joseph , Patel Uptal D , Hertz Julian T , Stanifer John W 
Published: November 2017

IntroductionSub-Saharan Africa is particularly vulnerable to the growing global burden of hypertension, but epidemiological studies are limited and barriers to optimal management are poorly understood. Therefore, we undertook a community-based mixed-methods study in Tanzania to investigate the epidemiology of hypertension and barriers to care.MethodsIn Northern Tanzania, between December 2013 and June 2015, we conducted a mixed-methods study, including a cross-sectional household epidemiological survey and qualitative sessions of focus groups and in-depth interviews. For the survey, we assessed for hypertension, defined as a single blood pressure ≥160/100 mm Hg, a two-time average of ≥140/90 mm Hg or current use of antihypertensive medications. To investigate relationships with potential risk factors, we used adjusted generalised linear models. Uncontrolled hypertension was defined as a two-time average measurement of ≥160/100 mm Hg irrespective of treatment status. Hypertension awareness was defined as a self-reported disease history in a participant with confirmed hypertension. To explore barriers to care, we identified emerging themes using an inductive approach within the framework method.ResultsWe enrolled 481 adults (median age 45 years) from 346 households, including 123 men (25.6%) and 358 women (74.4%). Overall, the prevalence of hypertension was 28.0% (95% CI 19.4% to 38.7%), which was independently associated with age >60 years (prevalence risk ratio (PRR) 4.68; 95% CI 2.25 to 9.74) and alcohol use (PRR 1.72; 95% CI 1.15 to 2.58). Traditional medicine use was inversely associated with hypertension (PRR 0.37; 95% CI 0.26 to 0.54). Nearly half (48.3%) of the participants were aware of their disease, but almost all (95.3%) had uncontrolled hypertension. In the qualitative sessions, we identified barriers to optimal care, including poor point-of-care communication, poor understanding of hypertension and structural barriers such as long wait times and undertrained providers.ConclusionsIn Northern Tanzania, the burden of hypertensive disease is substantial, and optimal hypertension control is rare. Transdisciplinary strategies sensitive to local practices should be explored to facilitate early diagnosis and sustained care delivery.
Effect of anti-podoplanin antibody administration during lipopolysaccharide-induced lung injury in mice
Authors: Lax Sian , Rayes Julie , Thickett David R , Watson Steve P 
Published: November 2017

IntroductionAcute respiratory distress syndrome (ARDS) is a devastating pulmonary condition in the critically ill patient. A therapeutic intervention is yet to be found that can prevent progression to ARDS. We recently demonstrated that the interaction between podoplanin expressed on inflammatory alveolar macrophages (iAMs) and its endogenous ligand, platelet C-type lectin-like 2 (CLEC-2), protects against exaggerated lung inflammation during a mouse model of ARDS. In this study, we aim to investigate the therapeutic use of a crosslinking/activating anti-podoplanin antibody (α-PDPN, clone 8.1.1) during lipopolysaccharide (LPS)-induced lung inflammation in mice.MethodsIntravenous administration of α-PDPN was performed 6 hours after intratracheal LPS in wildtype, C57Bl/6 mice. Lung function decline was measured by pulse oximetry as well as markers of local inflammation including bronchoalveolar lavage neutrophilia and cytokine/chemokine expression. In parallel, alveolar macrophages were isolated and cultured in vitro from haematopoietic-specific podoplanin-deficient mice (Pdpnfl/flVAV1cre+) and floxed-only controls treated with or without LPS in the presence or absence of α-PDPN.ResultsLung function decline as well as alveolar neutrophil recruitment was significantly decreased in mice treated with the crosslinking/activating α-PDPN in vivo. Furthermore, we demonstrate that, in vitro, activation of podoplanin on iAMs regulates their secretion of proinflammatory cytokines and chemokines.ConclusionsThese data confirm the importance of the CLEC-2–podoplanin pathway during intratracheal (IT)-LPS and demonstrate the beneficial effect of targeting podoplanin during IT-LPS in mice possibly via modulation of local cytokine/chemokine expression. Moreover, these data suggest that podoplanin-targeted therapies may have a beneficial effect in patients at risk of developing ARDS.
Copper deposition in focal nodular hyperplasia and inflammatory hepatocellular adenoma
Authors: Chandan Vishal S , Shah Sejal S , Mounajjed Taofic , Torbenson Michael S , Wu Tsung-Teh 
Published: November 2017

AimsTo examine copper deposition in focal nodular hyperplasia (FNH) and inflammatory hepatocellular adenoma (IHA) and to determine if it can play a role in their differentiation.Methods28 FNHs and 19 IHAs from surgical resections showing typical morphological and immunohistochemical features were stained with rhodanine to evaluate for copper deposition. Histological features such as nodularity, fibrous bands, ductular proliferation, steatosis, ballooned hepatocytes and lymphocytic inflammation were also scored.ResultsCopper deposition was detected in 96% (27/28) of FNHs and 37% (7/19) of IHAs, P<0.001. In all cases, copper was seen within the hepatocytes only around the pseudo-portal tracts or areas of fibrosis. Copper deposition in IHA was significantly associated with presence of lymphocytic inflammation (P=0.04) but not associated with features like nodularity, fibrous bands, ductular proliferation, ballooned hepatocytes and steatosis (P>0.05, for all). In FNH, the presence and degree of copper deposition was not significantly associated with any histological features (P>0.05, for all).ConclusionsCopper deposition occurs more frequently in FNH (96%) than IHA (37%), P<0.001. However, the presence of copper alone cannot be used as a feature to differentiate between FNH and IHA.
Retention of Interstitial Genes between TMPRSS2 and ERG Is Associated with Low-Risk Prostate Cancer
Authors: Murphy Stephen J. , Kosari Farhad , Karnes R. Jeffrey , Nasir Aqsa , Johnson Sarah H. , Gaitatzes Athanasios G. , Smadbeck James B. , Rangel Laureano J. , Vasmatzis George , Cheville John C. 
Published: November 2017

Abstract
TMPRSS2-ERG gene fusions occur in over 50% of prostate cancers, but their impact on clinical outcomes is not well understood. Retention of interstitial genes between TMPRSS2 and ERG has been reported to influence tumor progression in an animal model. In this study, we analyzed the status of TMPRSS2-ERG fusion genes and interstitial genes in tumors from a large cohort of men treated surgically for prostate cancer, associating alterations with biochemical progression. Through whole-genome mate pair sequencing, we mapped and classified rearrangements driving ETS family gene fusions in 133 cases of very low-, low-, intermediate-, and high-risk prostate cancer from radical prostatectomy specimens. TMPRSS2-ERG gene fusions were observed in 44% of cases, and over 90% of these fusions occurred in ERG exons 3 or 4. ERG fusions retaining interstitial sequences occurred more frequently in very low-risk tumors. These tumors also frequently displayed ERG gene fusions involving alternative 5′-partners to TMPRSS2, specifically SLC45A3 and NDRG1 and other ETS family genes, which retained interstitial TMPRSS2/ERG sequences. Lastly, tumors displaying TMPRSS2-ERG fusions that retained interstitial genes were less likely to be associated with biochemical recurrence (P = 0.028). Our results point to more favorable clinical outcomes in patients with ETS family fusion-positive prostate cancers, which retain potential tumor-suppressor genes in the interstitial regions between TMPRSS2 and ERG. Identifying these patients at biopsy might improve patient management, particularly with regard to active surveillance. Cancer Res; 77(22); 6157–67. ©2017 AACR.
Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma
Authors: Gide Tuba N. , Wilmott James S. , Scolyer Richard A. , Long Georgina V. 
Published: November 2017

AbstractImmune checkpoint inhibitors have revolutionized the treatment of patients with advanced-stage metastatic melanoma, as well as patients with many other solid cancers, yielding long-lasting responses and improved survival. However, a subset of patients who initially respond to immunotherapy, later relapse and develop therapy resistance (termed “acquired resistance”), whereas others do not respond at all (termed “primary resistance”). Primary and acquired resistance are key clinical barriers to further improving outcomes of patients with metastatic melanoma, and the known mechanisms underlying each involves various components of the cancer immune cycle, and interactions between multiple signaling molecules and pathways. Due to this complexity, current knowledge on resistance mechanisms is still incomplete. Overcoming therapy resistance requires a thorough understanding of the mechanisms underlying immune evasion by tumors. In this review, we explore the mechanisms of primary and acquired resistance to immunotherapy in melanoma and detail potential therapeutic strategies to prevent and overcome them. Clin Cancer Res; 24(6); 1260–70. ©2017 AACR.
Protein Kinase C Epsilon Is a Key Regulator of Mitochondrial Redox Homeostasis in Acute Myeloid Leukemia
Authors: Di Marcantonio Daniela , Martinez Esteban , Sidoli Simone , Vadaketh Jessica , Nieborowska-Skorska Margaret , Gupta Anushk , Meadows Jake M. , Ferraro Francesca , Masselli Elena , Challen Grant A. , Milsom Michael D. , Scholl Claudia , Fröhling Stefan , Balachandran Siddharth , Skorski Tomasz , Garcia Benjamin A. , Mirandola Prisco , Gobbi Giuliana , Garzon Ramiro , Vitale Marco , Sykes Stephen M. 
Published: November 2017

Abstract
Purpose: The intracellular redox environment of acute myeloid leukemia (AML) cells is often highly oxidized compared to healthy hematopoietic progenitors and this is purported to contribute to disease pathogenesis. However, the redox regulators that allow AML cell survival in this oxidized environment remain largely unknown.
Experimental Design: Utilizing several chemical and genetically-encoded redox sensing probes across multiple human and mouse models of AML, we evaluated the role of the serine/threonine kinase PKC-epsilon (PKCϵ) in intracellular redox biology, cell survival and disease progression.
Results: We show that RNA interference-mediated inhibition of PKCϵ significantly reduces patient-derived AML cell survival as well as disease onset in a genetically engineered mouse model (GEMM) of AML driven by MLL-AF9. We also show that PKCϵ inhibition induces multiple reactive oxygen species (ROS) and that neutralization of mitochondrial ROS with chemical antioxidants or co-expression of the mitochondrial ROS-buffering enzymes SOD2 and CAT, mitigates the anti-leukemia effects of PKCϵ inhibition. Moreover, direct inhibition of SOD2 increases mitochondrial ROS and significantly impedes AML progression in vivo. Furthermore, we report that PKCϵ over-expression protects AML cells from otherwise-lethal doses of mitochondrial ROS-inducing agents. Proteomic analysis reveals that PKCϵ may control mitochondrial ROS by controlling the expression of regulatory proteins of redox homeostasis, electron transport chain flux, as well as outer mitochondrial membrane potential and transport.
Conclusions: This study uncovers a previously unrecognized role for PKCϵ in supporting AML cell survival and disease progression by regulating mitochondrial ROS biology and positions mitochondrial redox regulators as potential therapeutic targets in AML. Clin Cancer Res; 24(3); 608–18. ©2017 AACR.
Optimized Prognosis Assessment in ST-Segment–Elevation Myocardial Infarction Using a Cardiac Magnetic Resonance Imaging Risk Score
Authors: Stiermaier Thomas , Jobs Alexander , de Waha Suzanne , Fuernau Georg , Pöss Janine , Desch Steffen , Thiele Holger , Eitel Ingo 
Published: November 2017

Background—
Cardiac magnetic resonance (CMR) demonstrated great potential for the prediction of major adverse cardiac events (MACE) in ST-segment–elevation myocardial infarction. The aim of this study was to develop and validate a CMR-based risk score for ST-segment–elevation myocardial infarction patients.

Methods and Results—

The scoring model was developed and validated on ST-segment–elevation myocardial infarction cohorts from 2 independent randomized controlled trials (n=738 and n=458 patients, respectively) and included left ventricular (LV) ejection fraction, infarct size, and microvascular obstruction. Primary end point was the 12-month MACE rate consisting of death, reinfarction, and new congestive heart failure. In the derivation cohort, LV ejection fraction ≤47%, infarct size ≥19%LV, and microvascular obstruction ≥1.4%LV were identified as the best cutoff values for MACE prediction. According to the hazard ratios in multivariable regression analysis, the CMR risk score was created by attributing 1 point for LV ejection fraction ≤47%, 1 point for infarct size ≥19%LV, and 2 points for microvascular obstruction ≥1.4%LV. In the validation cohort, the score showed a good prediction of MACE (area under the curve: 0.76). Stratification into a low (0/1 point) and high-risk group (≥2 points) resulted in significantly higher MACE rates in high-risk patients (9.0% versus 2.2%;
P
=0.001). Inclusion of the CMR score in addition to a model of clinical risk factors led to a significant increase of C statistics from 0.74 to 0.83 (
P
=0.037), a net reclassification improvement of 0.18 (
P
=0.009), and an integrated discriminative improvement of 0.04 (
P
=0.010).

Conclusions—
Our approach integrates the prognostic information of CMR imaging into a simple risk score that showed incremental prognostic value over clinical risk factors in ST-segment–elevation myocardial infarction patients.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT00712101 and NCT02158468.
Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment
Authors: Sun Yu-Yo , Lee Jolly , Huang Henry , Wagner Mary B. , Joiner Clinton H. , Archer David R. , Kuan Chia-Yi 
Published: November 2017

Background and Purpose—
The effects of lytic stroke therapy in patients with sickle cell anemia are unknown, although a recent study suggested that coexistent sickle cell anemia does not increase the risk of cerebral hemorrhage. This finding calls for systemic analysis of the effects of thrombolytic stroke therapy, first in humanized sickle mice, and then in patients. There is also a need for additional predictive markers of sickle cell anemia-associated vasculopathy.

Methods—
We used Doppler ultrasound to examine the carotid artery of Townes sickle mice tested their responses to repetitive mild hypoxia–ischemia- and transient hypoxia–ischemia-induced stroke at 3 or 6 months of age, respectively. We also examined the effects of tPA (tissue-type plasminogen activator) treatment in transient hypoxia–ischemia-injured sickle mice.

Results—
Three-month-old sickle cell (SS) mice showed elevated resistive index in the carotid artery and higher sensitivity to repetitive mild hypoxia–ischemia-induced cerebral infarct. Six-month-old SS mice showed greater resistive index and increased flow velocity without obstructive vasculopathy in the carotid artery. Instead, the cerebral vascular wall in SS mice showed ectopic expression of PAI-1 (plasminogen activator inhibitor-1) and P-selectin, suggesting a proadhesive and prothrombotic propensity. Indeed, SS mice showed enhanced leukocyte and platelet adherence to the cerebral vascular wall, broader fibrin deposition, and higher mortality after transient hypoxia–ischemia. Yet, post-transient hypoxia–ischemia treatment with tPA reduced thrombosis and mortality in SS mice.

Conclusions—
Sickle mice are sensitive to hypoxia/ischemia-induced cerebral infarct but benefit from thrombolytic treatment. An increased resistive index in carotid arteries may be an early marker of sickle cell vasculopathy.
Whole Grain Consumption and Risk of Ischemic Stroke
Authors: Juan Juan , Liu Gang , Willett Walter C. , Hu Frank B. , Rexrode Kathryn M. , Sun Qi 
Published: November 2017

Background and Purpose—
Higher intake of whole grains may exert cardiometabolic benefits, although findings on stroke risk are inconclusive. The potentially differential effects of individual whole grain foods on ischemic stroke have not been examined.

Methods—
We analyzed whole grain consumption in relation to ischemic stroke among 71 750 women from the Nurses’ Health Study and 42 823 men from the Health Professionals Follow-up Study who were free of cardiovascular disease, diabetes mellitus, and cancer at baseline (1984 and 1986, respectively) through 2010 using a Cox proportional hazards model. Validated semiquantitative food frequency questionnaires were used to assess consumption of whole grain intake, including whole grain cold breakfast cereal, dark bread, oatmeal, brown rice, popcorn, bran, and germ. Self-reported incident cases of ischemic stroke were confirmed through medical record review.

Results—

During 2 820 128 person-years of follow-up in the 2 cohorts, 2458 cases of ischemic stroke were identified and confirmed. Intake of total whole grains was not associated with risk of ischemic stroke after adjustment for covariates: the pooled hazard ratio (95% confidence interval) comparing extreme intake levels was 1.04 (0.91–1.19). However, intake of whole grain cold breakfast cereal and total bran was inversely associated with ischemic stroke after multivariate adjustment: the pooled hazard ratios (95% confidence intervals) were 0.88 (0.80–0.96;
P
trend
=0.008) and 0.89 (0.79–1.00;
P
trend
=0.004), respectively. Other whole grain foods were not associated with a lower risk of ischemic stroke.

Conclusions—
Although overall consumption of whole grains was not associated with lower risk of ischemic stroke, greater consumption of whole grain cold breakfast cereal and bran was significantly associated with a lower risk of ischemic stroke. More studies are needed to replicate these associations between individual whole grain foods and risk of ischemic stroke among other populations.
Collingwood, Scientism and Historicism
Authors: D’Oro Giuseppina , Connelly James 
Published: November 2017

Abstract
The philosophy of history is undergoing something of a revival. Much has happened since its heyday in the 1960s when methodological discussions concerning the structure of explanation in history and the natural sciences were central to the philosophical agenda. This introduction revisits Collingwood’s contribution to the philosophy of history, his views on the relation between science and history, and the possibility of historical knowledge suggesting his work is of enduring relevance to contemporary debates. It locates his contribution in the context of the hermeneutic tradition and locates his defence of the methodological autonomy of history in the context of recent debates concerning the relation between science and the history of the philosophy of science.
Collingwood, Idealism, Realism, and the Possibility of Historical Knowledge
Authors: Lord Timothy C. 
Published: November 2017

Abstract
Collingwood argued that most theories of knowledge in English, up to his time, had been based on perception and scientific thinking; thus, if true, they made history impossible. So how is historical knowledge possible? Collingwood argued that only an idealistic philosophy can account for the possibility of historical knowledge. Consequently he integrated with his idealist theory of history a forceful and damaging critique of the “naive realism” of his day. In this paper I defend Collingwood’s idealist answer to this question, demonstrating how he hoped to broaden the scope of English epistemology through his anti-realist philosophy of history. I also analyze a recently theorized and purportedly more sophisticated form of historical realism which has been theorized by Chris Lorenz. Lorenz borrows Putnam’s notion of internal realism to argue for a historical realism which can account for knowledge of the real past. I argue that internal realism fails as historical realism. Collingwood’s idealism is a better response to relativism as well as naive realism than is internal realism. I conclude that Collingwood’s answer to the question of historical knowledge – which as I show, is Kantian in character – demanded of him, and perhaps demands of us today, a break with the dominant philosophies of perception, truth, and logic.
Collingwood, Bradley, and Critical History
Authors: DeVall Robert F. 
Published: November 2017

Abstract
Collingwood argues in The Idea of History that we should reject the common-sense theory of history because it uses what he calls the “scissors and paste” approach that connects the reports of authorities about past events without critical analysis. Collingwood proclaims that Bradley initiates a Copernican revolution in history that makes the historian and his or her experiences the judge and jury of the eyewitnesses. However, he believes Bradley is silent concerning the constructive element that “fills the gaps” left behind in the records of the past. I believe Collingwood may have overlooked this aspect of Bradley’s thought because, if we look to passages in The Presuppositions, he implicitly argues for a constructive element along with the critical attitude. Since both think history is critical, their agreement on the historian being the criterion brings up interesting philosophical problems concerning subjectivism.
A Consistent Sea-Level Reconstruction and Its Budget on Basin and Global Scales over 1958–2014
Authors: Frederikse Thomas , Jevrejeva Svetlana , Riva Riccardo E. M. , Dangendorf Sönke 
Published: November 2017

AbstractDifferent sea level reconstructions show a spread in sea level rise over the last six decades and it is not yet certain whether the sum of contributors explains the reconstructed rise. Possible causes for this spread are, among others, vertical land motion at tide-gauge locations and the sparse sampling of the spatially variable ocean. To assess these open questions, reconstructed sea level and the role of the contributors are investigated on a local, basin, and global scale. High-latitude seas are excluded. Tide-gauge records are combined with observations of vertical land motion, independent estimates of ice-mass loss, terrestrial water storage, and barotropic atmospheric forcing in a self-consistent framework to reconstruct sea level changes on basin and global scales, which are compared to the estimated sum of contributing processes. For the first time, it is shown that for most basins the reconstructed sea level trend and acceleration can be explained by the sum of contributors, as well as a large part of the decadal variability. The sparsely sampled South Atlantic Ocean forms an exception. The global-mean sea level reconstruction shows a trend of 1.5 ± 0.2 mm yr−1 over 1958–2014 (1σ), compared to 1.3 ± 0.1 mm yr−1 for the sum of contributors. Over the same period, the reconstruction shows a positive acceleration of 0.07 ± 0.02 mm yr−2, which is also in agreement with the sum of contributors, which shows an acceleration of 0.07 ± 0.01 mm yr−2. Since 1993, both reconstructed sea level and the sum of contributors show good agreement with altimetry estimates.