bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Promotion of Breast Cancer Metastasis Caused by Inhibition of CSF-1R/CSF-1 Signaling Is Blocked by Targeting the G-CSF Receptor
Authors: Swierczak Agnieszka , Cook Andrew D. , Lenzo Jason C. , Restall Christina M. , Doherty Judy P. , Anderson Robin L. , Hamilton John A. 
Published: April 2014

AbstractTreatment options are limited for patients with breast cancer presenting with metastatic disease. Targeting of tumor-associated macrophages through the inhibition of colony-stimulating factor-1 receptor (CSF-1R), a key macrophage signaling pathway, has been reported to reduce tumor growth and metastasis, and these treatments are now in clinical trials. Here, we report that, surprisingly, treatment with neutralizing anti–CSF-1R and anti–CSF-1 antibodies, or with two different small-molecule inhibitors of CSF-1R, could actually increase spontaneous metastasis without altering primary tumor growth in mice bearing two independently derived mammary tumors. The blockade of CSF-1R or CSF-1 led to increased levels of serum G-CSF, increased frequency of neutrophils in the primary tumor and in the metastasis-associated lung, as well as increased numbers of neutrophils and Ly6Chi monocytes in the peripheral blood. Neutralizing antibody against the G-CSF receptor, which regulates neutrophil development and function, reduced the enhanced metastasis and neutrophil numbers that resulted from CSF-1R blockade. These results indicate that the role of the CSF-1R/CSF-1 system in breast cancer is far more complex than originally proposed, and requires further investigation as a therapeutic target. Cancer Immunol Res; 2(8); 765–76. ©2014 AACR.
Response to BRAF Inhibition in Melanoma Is Enhanced When Combined with Immune Checkpoint Blockade
Authors: Cooper Zachary A. , Juneja Vikram R. , Sage Peter T. , Frederick Dennie T. , Piris Adriano , Mitra Devarati , Lo Jennifer A. , Hodi F. Stephen , Freeman Gordon J. , Bosenberg Marcus W. , McMahon Martin , Flaherty Keith T. , Fisher David E. , Sharpe Arlene H. , Wargo Jennifer A. 
Published: April 2014

Abstract
BRAF-targeted therapy results in objective responses in the majority of patients; however, the responses are short lived (∼6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but the responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8+ T-cell infiltrate and a decrease in immunosuppressive cytokines. There is also increased expression of the immunomodulatory molecule PDL1, which may contribute to the resistance. On the basis of these findings, we hypothesized that BRAF-targeted therapy may synergize with the PD1 pathway blockade to enhance antitumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten−/− syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8+ T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model, CD8+ T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD1 or anti-PDL1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor-infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions still remain unanswered. Further studies using this new melanoma mouse model may provide therapeutic insights, including optimal timing and sequence of therapy. Cancer Immunol Res; 2(7); 643–54. ©2014 AACR.
Determinants of Heat Generation in Patients Treated With Therapeutic Hypothermia Following Cardiac Arrest
Authors: Murnin Matthew R. , Sonder Petra , Janssens Gladys N. , Henry Connie L. , Polderman Kees H. , Rittenberger Jon C. , Dezfulian Cameron ,   And the Post Cardiac Arrest Service
Published: April 2014

Background

Therapeutic hypothermia (
TH
) is recommended to reduce ischemic brain injury after cardiac arrest. The variables that predict heat generation by patients receiving
TH
are uncertain, as is how this heat generation relates to neurologic outcome. We hypothesized that patient characteristics, medication use, inflammation, and organ injury would be associated with heat generation. We further hypothesized that neurologic outcome would be most strongly associated with heat generation.

Methods and Results

Surface and intravascular cooling devices were used to provide
TH
in 57 consecutive cardiac arrest patients. Device water temperatures during the maintenance (33°C) phase were collected. Patient heat generation was quantified as the “heat index” (
HI
), which was the inverse average water temperature over a minimum of 2 hours of maintenance hypothermia. Variables measuring reduced ischemic injury and improved baseline health were significantly associated with
HI
. After controlling for presenting rhythm, a higher
HI
was independently associated with favorable disposition (
OR
=2.2; 95%
CI
1.2 to 4.1;
P
=0.014) and favorable Cerebral Performance Category (
OR
=1.8; 95%
CI
1.0 to 3.1;
P
=0.035). Higher
HI
predicted favorable disposition (receiver‐operator area under the curve 0.71,
P
=0.029).
HI
was linearly correlated with arteriovenous
CO
2
(
r
=0.69;
P
=0.041) but not O
2
(
r
=0.13;
P
=0.741) gradients.

Conclusions

In cardiac arrest patients receiving
TH
, greater heat generation is associated with better baseline health, reduced ischemic injury, and improved neurologic function, which results in higher metabolism.
HI
can control for confounding effects of patient heat generation in future clinical trials of rapid
TH
and offers early prognostic information.
Association of Comorbidity Burden With Abnormal Cardiac Mechanics: Findings From the HyperGEN Study
Authors: Selvaraj Senthil , Aguilar Frank G. , Martinez Eva E. , Beussink Lauren , Kim Kwang‐Youn A. , Peng Jie , Rasmussen‐Torvik Laura , Sha Jin , Irvin Marguerite R. , Gu C. Charles , Lewis Cora E. , Hunt Steven C. , Arnett Donna K. , Shah Sanjiv J. 
Published: April 2014

Background

Comorbidities are common in heart failure (
HF
), and the number of comorbidities has been associated with poor outcomes in
HF
patients. However, little is known about the effect of multiple comorbidities on cardiac mechanics, which could impact the pathogenesis of
HF
. We sought to determine the relationship between comorbidity burden and adverse cardiac mechanics.

Methods and Results

We performed speckle‐tracking analysis on echocardiograms from the HyperGEN study (n=2150). Global longitudinal, circumferential, and radial strain, and early diastolic (e') tissue velocities were measured. We evaluated the association between comorbidity number and cardiac mechanics using linear mixed effects models to account for relatedness among subjects. The mean age was 51±14 years, 58% were female, and 47% were African American. Dyslipidemia and hypertension were the most common comorbidities (61% and 58%, respectively). After adjusting for left ventricular (
LV
) mass index, ejection fraction, and several potential confounders, the number of comorbidities remained associated with all indices of cardiac mechanics except global circumferential strain (eg, β=−0.32 [95%
CI
−0.44, −0.20] per 1‐unit increase in number of comorbidities for global longitudinal strain; β=−0.16 [95%
CI
−0.20, −0.11] for e' velocity;
P
≤0.0001 for both comparisons). Results were similar after excluding participants with abnormal
LV
geometry (
P
<0.05 for all comparisons).

Conclusions

Higher comorbidity burden is associated with worse cardiac mechanics, even in the presence of normal
LV
geometry. The deleterious effect of multiple comorbidities on cardiac mechanics may explain both the high comorbidity burden and adverse outcomes in patients who ultimately develop
HF
.
Prognostic Value of Left Ventricular Diastolic Dysfunction in a General Population
Authors: Kuznetsova Tatiana , Thijs Lutgarde , Knez Judita , Herbots Lieven , Zhang Zhenyu , Staessen Jan A. 
Published: April 2014

Background

New techniques of Tissue Doppler Imaging (
TDI
) enable the measurement of myocardial velocities and provide information about left ventricular (
LV
) diastolic function. Recent studies explored the prognostic role of
TDI
‐derived indexes. However, these studies considered only total mortality and did not provide information on cardiovascular mortality and morbidity. Therefore, we investigated in continuous and categorical analyses whether Doppler diastolic indexes contained any prognostic information over and beyond traditional cardiovascular risk factors in a general population.

Methods and Results

We measured early and late diastolic peak velocities of mitral inflow (E and A) by conventional Doppler, and the mitral annular velocities (e' and a') by
TDI
in 793 participants (mean age 50.9 years). We calculated multivariable‐adjusted hazard ratios for conventional and
TDI
Doppler indexes, while accounting for family cluster and cardiovascular risk factors. Median follow‐up was 4.8 years (5th to 95th percentile, 3.0 to 5.4). With adjustments applied for covariables, e' velocity was a significant predictor of fatal and nonfatal cardiovascular (n=59;
P
=0.004) and cardiac events (n=40;
P
=0.001).
TDI
e' yielded a net reclassification improvement of 54.2% for cardiovascular and 64.0% for cardiac events. Hazard ratios of all cardiovascular (2.21;
P
=0.042) and cardiac (4.50;
P
=0.002) events were significantly elevated in participants with increased
LV
filling pressure compared with subjects with normal diastolic function.

Conclusions

TDI
e' velocity is a significant predictor of fatal and nonfatal cardiovascular events in a general population. Furthermore, we observed an increase in all cardiovascular events in the diastolic dysfunction group characterized by elevated
LV
filling pressure.
White Matter Hyperintensities and Their Penumbra Lie Along a Continuum of Injury in the Aging Brain
Authors: Maillard Pauline , Fletcher Evan , Lockhart Samuel N. , Roach Alexandra E. , Reed Bruce , Mungas Dan , DeCarli Charles , Carmichael Owen T. 
Published: April 2014

Background and Purpose—
Aging is accompanied by clinically silent cerebral white matter injury identified through white matter hyperintensities (WMHs) on fluid-attenuated inversion recovery (FLAIR)– and diffusion tensor imaging–based measures of white matter integrity. The temporal course of FLAIR and diffusion tensor imaging changes within WMHs and their less-injured periphery (ie, their penumbra), however, has not been fully studied. We used longitudinal diffusion tensor imaging and FLAIR to explore these changes.

Methods—
One hundred fifteen participants, aged 73.7±6.7 years, received clinical evaluations and MRIs on 2 dates. WMHs and fractional anisotropy (FA) maps were produced from FLAIR and diffusion tensor imaging and coregistered to a standardized space. Each distinct WMH was categorized as growing, stagnant, or noncontiguous incident. The penumbra of each WMH was similarly categorized as corresponding to a stagnant, growing, or noncontiguous incident WMH. Linear mixed-effect models were used to assess whether FA and FLAIR measurements changed between baseline and follow-up and differed between tissue categories.

Results—
Baseline FA differed significantly by tissue category, with the following ordering of categories from highest to lowest FA: penumbra of noncontiguous incident, then stagnant, then growing WMHs; noncontiguous incident, then stagnant, then growing WMHs. Despite differences in baseline values, all tissue categories experienced declines in FA over time. Only noncontiguous incident WMHs showed significant FLAIR signal increases over time, and FLAIR signal significantly decreased in stagnant WMHs.

Conclusions—
WMHs and their penumbra vary in severity and together span a continuous spectrum of white matter injury that worsens with time. FLAIR fails to capture this continuous injury process fully but does identify a subclass of lesions that seem to improve over time.
Xenophon contra Plato: Citizen Motivation and Socratic Biography
Authors: Vandiver Josh 
Published: April 2014

Abstract
Xenophon’s Cyropaedia should be considered a classic text of political theory. It inaugurated the political biography and is one of the most extensive classical Greek works on political leadership. It has, however, been neglected or, when studied, misunderstood as a cautionary tale of political corruption. I argue that Xenophon’s method in the Cyropaedia is illustrative of Socratic biography and focused on three problems: why leaders emerge, what motivates them, and how their character is constituted. Xenophon responds to these questions by modelling a spirited character type, a person uniquely motivated by philotimia, the desire for political status and honour, and thus uniquely suited for development into a political leader. Furthermore, Xenophon is in theoretic dialogue with Plato over the concepts which comprise this model and a proper understanding of their dialogue impacts interpretations of the Cyropaedia as a whole, Xenophon’s intervention in Greek political discourse, and Plato’s influence on contemporaries.
Impact of Bay-Breeze Circulations on Surface Air Quality and Boundary Layer Export
Authors: Loughner Christopher P. , Tzortziou Maria , Follette-Cook Melanie , Pickering Kenneth E. , Goldberg Daniel , Satam Chinmay , Weinheimer Andrew , Crawford James H. , Knapp David J. , Montzka Denise D. , Diskin Glenn S. , Dickerson Russell R. 
Published: April 2014

AbstractMeteorological and air-quality model simulations are analyzed alongside observations to investigate the role of the Chesapeake Bay breeze on surface air quality, pollutant transport, and boundary layer venting. A case study was conducted to understand why a particular day was the only one during an 11-day ship-based field campaign on which surface ozone was not elevated in concentration over the Chesapeake Bay relative to the closest upwind site and why high ozone concentrations were observed aloft by in situ aircraft observations. Results show that southerly winds during the overnight and early-morning hours prevented the advection of air pollutants from the Washington, D.C., and Baltimore, Maryland, metropolitan areas over the surface waters of the bay. A strong and prolonged bay breeze developed during the late morning and early afternoon along the western coastline of the bay. The strength and duration of the bay breeze allowed pollutants to converge, resulting in high concentrations locally near the bay-breeze front within the Baltimore metropolitan area, where they were then lofted to the top of the planetary boundary layer (PBL). Near the top of the PBL, these pollutants were horizontally advected to a region with lower PBL heights, resulting in pollution transport out of the boundary layer and into the free troposphere. This elevated layer of air pollution aloft was transported downwind into New England by early the following morning where it likely mixed down to the surface, affecting air quality as the boundary layer grew.
The friends and family test: a qualitative study of concerns that influence the willingness of English National Health Service staff to recommend their organisation
Authors: Dixon-Woods Mary , Minion Joel T , McKee Lorna , Willars Janet , Martin Graham 
Published: April 2014

Objectives The views of practitioners at the ‘sharp end’ of care provision are increasingly recognised as important indicators of quality of care. The National Health Service (NHS) Staff Survey in England has quantified employees' views on how far they would be happy with the standard of care provided by their organisation if a friend or family member needed treatment. We aimed to characterise the concerns that might affect the willingness of staff to recommend their own organisations. Design Qualitative study involving semi-structured interviews. Data analysis based on the constant comparative method. Participants Members of clinical and managerial staff in four NHS organisations ( n = 70), and senior stakeholders across the NHS including clinicians, managers and others with a strategic or senior-level perspective ( n = 98). Setting One hundred and sixty-eight interviews were conducted: 70 in four case study organisations and 98 across the wider English NHS. Main outcome measures Not applicable. Results Asking study participants the ‘if a friend…’ question offered insider views on the quality of care. Some staff had no concerns, but others, identified significant problems with consistency, reliability and behaviour of staff. Participants identified reasons for poor care that included inadequate organisational systems; structural problems of understaffing and under-resourcing; weaknesses in professional cultures and professional competence and failure to deal with problems such as unacceptable conduct. Participants emphasised that staff were not always able to deliver high-quality care because they worked in difficult conditions. Conclusions Asking staff to give accounts of their willingness to recommend their organisation to family and friends elicits important insights into quality and safety of care. Such accounts might be able to provide warning signs that could signal organisational decline and avert healthcare scandals, but use outside a research context requires further evaluation.
Learning from preventable deaths: exploring case record reviewers' narratives using change analysis
Authors: Hogan Helen , Healey Frances , Neale Graham , Thomson Richard , Black Nick , Vincent Charles 
Published: April 2014

Objective To determine if applying change analysis to the narrative reports made by reviewers of hospital deaths increases the utility of this information in the systematic analysis of patient harm. Design Qualitative analysis of causes and contributory factors underlying patient harm in 52 case narratives linked to preventable deaths derived from a retrospective case record review of 1000 deaths in acute National Health Service Trusts in 2009. Participants 52 preventable hospital deaths. Setting England. Main outcome measures The nature of problems in care and contributory factors underlying avoidable deaths in hospital. Results The change analysis approach enabled explicit characterisation of multiple problems in care, both across the admission and also at the boundary between primary and secondary care, and illuminated how these problems accumulate to cause harm. It demonstrated links between problems and underlying contributory factors and highlighted other threats to quality of care such as standards of end of life management. The method was straightforward to apply to multiple records and achieved good inter-rater reliability. Conclusion Analysis of case narratives using change analysis provided a richer picture of healthcare-related harm than the traditional approach, unpacking the nature of the problems, particularly by delineating omissions from acts of commission, thus facilitating more tailored responses to patient harm.
Audiometric Outcome Comparison between Titanium Prosthesis and Molded Autologous Material
Authors: Órfão Tiago , Júlio Sara , Ramos José Filipe , Dias Cláudia Camila , Silveira Helena , Santos Margarida 
Published: April 2014

ObjectiveTo evaluate and compare the audiometric outcomes of ossicular reconstruction with titanium prosthesis and autologous material.Study DesignRetrospective cohort study.SettingTertiary referral center.Subjects and MethodsAudiometric results of consecutive patients who performed ossiculoplasty with titanium prosthesis (n = 43) or autologous material (n = 48), from October 2008 to December 2011, were reviewed retrospectively and compared. The association between air‐bone gain and age, ossiculoplasty material (autologous or titanium), preoperative diagnosis (chronic otitis media without cholesteatoma, cholesteatoma, or conductive hearing loss with intact tympanic membrane), and type of surgery (tympanoplasty, canal wall‐down mastoidectomy, or canal wall‐up mastoidectomy) was explored using regression analysis.ResultsPreoperative audiometric evaluation did not show differences between titanium and autologous groups in air‐bone gap and pure‐tone average. A postoperative decrease of 11.0 dB in air‐bone gap and 12.4 dB in pure‐tone average was observed in titanium ossiculoplasty compared with a reduction of 4.0 dB in air‐bone gap and 5.1 dB in pure‐tone average when autologous reconstruction was used. Mann‐Whitney test revealed superior results in the titanium group compared with autologous reconstruction patients in air‐bone gap (P =. 02) and pure‐tone average (P =. 02). However, no statistically significant associations were observed after multivariate linear regression analysis of air‐bone gap gain when adjusted for age, ossiculoplasty material, type of surgery, and preoperative diagnosis. One titanium prosthesis extrusion occurred during follow‐up (2%).ConclusionAudiometric results achieved by titanium prosthesis are promising, but significant differences compared with autologous ossiculoplasty were not present.
The DEXMART hand: Mechatronic design and experimental evaluation of synergy-based control for human-like grasping
Authors: Palli G. , Melchiorri C. , Vassura G. , Scarcia U. , Moriello L. , Berselli G. , Cavallo A. , De Maria G. , Natale C. , Pirozzi S. , May C. , Ficuciello F. , Siciliano B. 
Published: April 2014

This paper summarizes recent activities carried out for the development of an innovative anthropomorphic robotic hand called the DEXMART Hand. The main goal of this research is to face the problems that affect current robotic hands by introducing suitable design solutions aimed at achieving simplification and cost reduction while possibly enhancing robustness and performance. While certain aspects of the DEXMART Hand development have been presented in previous papers, this paper is the first to give a comprehensive description of the final hand version and its use to replicate human-like grasping. In this paper, particular emphasis is placed on the kinematics of the fingers and of the thumb, the wrist architecture, the dimensioning of the actuation system, and the final implementation of the position, force and tactile sensors. The paper focuses also on how these solutions have been integrated into the mechanical structure of this innovative robotic hand to enable precise force and displacement control of the whole system. Another important aspect is the lack of suitable control tools that severely limits the development of robotic hand applications. To address this issue, a new method for the observation of human hand behavior during interaction with common day-to-day objects by means of a 3D computer vision system is presented in this work together with a strategy for mapping human hand postures to the robotic hand. A simple control strategy based on postural synergies has been used to reduce the complexity of the grasp planning problem. As a preliminary evaluation of the DEXMART Hand’s capabilities, this approach has been adopted in this paper to simplify and speed up the transfer of human actions to the robotic hand, showing its effectiveness in reproducing human-like grasping.