bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measuring the Pain Area: An Intra‐ and Inter‐Rater Reliability Study Using Image Analysis Software
Authors: dos Reis Felipe Jose Jandre , de Barros e Silva Veronica , de Lucena Raphaela Nunes , Mendes Cardoso Bruno Alexandre , Nogueira Leandro Calazans 
Published: December 2014

AbstractPain drawings have frequently been used for clinical information and research. The aim of this study was to investigate intra‐ and inter‐rater reliability of area measurements performed on pain drawings. Our secondary objective was to verify the reliability when using computers with different screen sizes, both with and without mouse hardware. Pain drawings were completed by patients with chronic neck pain or neck–shoulder–arm pain. Four independent examiners participated in the study. Examiners A and B used the same computer with a 16‐inch screen and wired mouse hardware. Examiner C used a notebook with a 16‐inch screen and no mouse hardware, and Examiner D used a computer with an 11.6‐inch screen and a wireless mouse. Image measurements were obtained using GIMP and NIH ImageJ computer programs. The length of all the images was measured using GIMP software to a set scale in ImageJ. Thus, each marked area was encircled and the total surface area (cm2) was calculated for each pain drawing measurement. A total of 117 areas were identified and 52 pain drawings were analyzed. The intrarater reliability between all examiners was high (ICC = 0.989). The inter‐rater reliability was also high. No significant differences were observed when using different screen sizes or when using or not using the mouse hardware. This suggests that the precision of these measurements is acceptable for the use of this method as a measurement tool in clinical practice and research.
Kelsen's Theory on International Law during His Exile in Geneva
Authors: Losano Mario G. 
Published: December 2014

AbstractKelsen's monistic theory of international law was shaped during his exile in Geneva (1933–1940), but its deep roots are to be found in his Pure Theory of Law, centred on the neo‐Kantian notion of “system.” According to this conception, a legal system can only descend from a single principle. Consequently, Kelsen constructed a monistic theory of law, i.e., a legal system incorporating all norms into a pyramidal structure culminating in a single principle: the fundamental norm. This Kelsenian pyramid must also include international law, considering that if international law were a legal system different from national law (as the dualistic theory assumes), the theoretical construction would need two fundamental norms. This dualism is as incompatible with Kelsen's monistic vision as Schmitt's theory of “Great Spaces,” creating a hierarchical system of international relations. In the Kelsenian pyramid, international law occupies a position superior to national law: The consequences of this assumption are discussed in some documents recently published in German and French.
Validation of an Activity Monitor in Older Inpatients Undergoing Slow Stream Rehabilitation
Authors: Raymond Melissa , Winter Adele , Holland Anne E. 
Published: December 2014

Background:Older adults undergoing rehabilitation may have limited mobility, slow gait speeds and low levels of physical activity. Devices used to quantify activity levels in older adults must be able to detect these characteristics.Objective:To investigate the validity of the Positional Activity Logger (PAL2) for monitoring position and measuring physical activity in older inpatients (slow stream rehabilitation).Methods:Twelve older inpatients (≥65 years) underwent a 1-hour protocol (set times in supine, sitting, standing; stationary and moving). Participants were video-recorded while wearing the PAL2. Time spent in positions and walking (comfortable and fast speeds) were ascertained through video-recording analysis and compared with PAL2 data.Results:There was no difference between the PAL2 and video recording for time spent in any position (P-values 0.055 to 0.646). Walking speed and PAL2 count were strongly correlated (Pearson’s r = .913, P < .01). The PAL2 was responsive to within-person changes in gait speed: activity count increased by an average of 52.47 units (95% CI 3.31, 101.63). There was 100% agreement for transitions between lying to sitting and < 1 transition difference between siting to standing.Conclusion:The PAL2 is a valid tool for quantifying activity levels, position transitions, and within-person changes in gait speed in older inpatients.
Effect of L-type calcium channel blocker (amlodipine) on myocardial iron deposition in patients with thalassaemia with moderate-to-severe myocardial iron deposition: protocol for a randomised, controlled trial
Authors: Shakoor Amarah , Zahoor Maaman , Sadaf Alina , Alvi Najveen , Fadoo Zehra , Rizvi Arjumand , Quadri Farheen , Tipoo Fateh Ali , Khurshid Mohammad , Sajjad Zaffar , Colan Steven , Hasan Babar S 
Published: December 2014

IntroductionSideroblastic cardiomyopathy secondary to repeated blood transfusions is a feared complication in thalassaemia. Control of myocardial iron is thus becoming the cornerstone of thalassaemia management. Recent evidence suggests a role for L-type Ca2+channels in mediating iron uptake by the heart. Blocking the cellular iron uptake through these channels may add to the benefit of therapy to standard chelation in reducing myocardial iron. We aim to determine the efficacy of amlodipine (a calcium channel blocker) as an adjunct to standard aggressive chelation in retarding myocardial iron deposition in thalassaemics with or without cardiomyopathy.OutcomesThe primary outcome is to compare the efficacy of amlodipine+chelation (intervention) versus standard chelation (control) in retarding myocardial iron deposition. Secondary outcomes include the effect of amlodipine therapy on systolic and diastolic function, strain and strain rate and liver iron content.Methods and analysisThis is a single-centre, parallel-group, prospective randomised control trial. Twenty patients will be randomised in a 1:1 allocation ratio into the intervention and control arms. In addition to conventional echocardiography, MRI T2* values for assessment of cardiac and liver iron load will be obtained at baseline and at 6 and 12 months. Cardiac T2* will be reported as the geometric mean and per cent coefficient of variation, and an increase in cardiac T2* values from baseline will be used as an end point to compare the efficacy of therapy. A p Value of <0.05 will be considered significant.Study settingDepartment of Pediatric and Child Health, Aga Khan University Hospital, Karachi, Pakistan.Ethics and disseminationThis study has been approved by the Ethics Review Committee and Clinical Trials Unit at The Aga Khan University with respect to scientific content and compliance with applicable research and human subjects regulations. Findings will be reported through scientific publications and research conferences and project summary papers for participants.Trial registration numberClinicalTrials.Gov. Registration no:NCT02065492.
Innovations in Statistical Physics
Authors: Kadanoff Leo P. 
Published: December 2014

In 1963–71, a group of people, myself included, formulated and perfected a new approach to physics problems, which eventually came to be known under the names of scaling, universality, and renormalization. This work formed the basis of a wide variety of theories ranging from a starting point in critical phenomena, moving out to particle physics and relativity, and then into economics and biology. This work was of transcendental beauty and of considerable intellectual importance.This left me with a personal problem. What next? Constructing the answer to that question would dominate the next 45 years of my professional life. I would ■ Try to help in finding and constructing new fields of science. ■ Do research and give talks on the science-society borderline. ■ Provide constructive criticism of scientific and technical work. ■ Help students and younger scientists. ■ Demonstrate scientific leadership.
Novel Mechanism of Macrophage-Mediated Metastasis Revealed in a Zebrafish Model of Tumor Development
Authors: Wang Jian , Cao Ziquan , Zhang Xing-Mei , Nakamura Masaki , Sun Meili , Hartman Johan , Harris Robert A. , Sun Yuping , Cao Yihai 
Published: December 2014

Abstract
Cancer metastasis can occur at early stages of tumor development due to facilitative alterations in the tumor microenvironment. Although imaging techniques have considerably improved our understanding of metastasis, early events remain challenging to study due to the small numbers of malignant cells involved that are often undetectable. Using a novel zebrafish model to investigate this process, we discovered that tumor-associated macrophages (TAM) acted to facilitate metastasis by binding tumor cells and mediating their intravasation. Mechanistic investigations revealed that IL6 and TNFα promoted the ability of macrophages to mediate this step. M2 macrophages were particularly potent when induced by IL4, IL10, and TGFβ. In contrast, IFNγ-lipopolysaccharide–induced M1 macrophages lacked the capability to function in the same way in the model. Confirming these observations, we found that human TAM isolated from primary breast, lung, colorectal, and endometrial cancers exhibited a similar capability in invasion and metastasis. Taken together, our work shows how zebrafish can be used to study how host contributions can facilitate metastasis at its earliest stages, and they reveal a new macrophage-dependent mechanism of metastasis with possible prognostic implications. Cancer Res; 75(2); 306–15. ©2014 AACR.
The Association of Age and Race and the Risk of Large Bowel Polyps
Authors: Wallace Kristin , Burke Carol A. , Ahnen Dennis J. , Barry Elizabeth L. , Bresalier Robert S. , Saibil Fred , Baron John A. 
Published: December 2014

Abstract
Background: Blacks have a higher incidence of colorectal cancer and a younger age at diagnosis compared with whites. Few studies have investigated racial differences in risk of metachronous adenomas and serrated polyps and whether this risk differs by polyp characteristics or age of patient.
Methods: We analyzed data pooled from three placebo-controlled adenoma chemoprevention trials to explore racial differences in the risk of large bowel polyps in patients ≤50 and &gt;50 years of age. Using generalized linear regression, we estimated risk ratios (RR) and 95% confidence intervals (CI) as measures of the association between race and risk of one or more adenomas or serrated polyps after randomization.
Results: Among the 2,605 subjects who completed at least one follow-up exam, blacks ≤50 years of age had a higher risk of any conventional adenoma (RR, 1.70; 95% CI, 0.99–2.92) and advanced neoplasms (RR, 4.05; 95% CI, 1.43–11.46) and a nonsignificantly lower risk of serrated polyps (RR, 0.75; 95% CI, 0.34–1.62) compared with whites. Among patients &gt;50 years, there was no racial difference in risk of adenomas (RR, 1.08; 95% CI, 0.92–1.27) or advanced neoplasms (RR, 1.05; 95% CI, 0.71- 1.56). However, blacks had a significantly lower risk of serrated polyps (RR, 0.65; 95% CI, 0.49–0.87) than whites.
Conclusions: Our results demonstrate a higher risk of metachronous adenomas in blacks compared with whites at younger ages.
Impact: Our results suggest that the racial disparity in colorectal cancer incidence may be due to an excess of neoplasia in younger blacks. Cancer Epidemiol Biomarkers Prev; 24(2); 448–53. ©2014 AACR.
MET Amplification Status in Therapy-Naïve Adeno- and Squamous Cell Carcinomas of the Lung
Authors: Schildhaus Hans-Ulrich , Schultheis Anne M. , Rüschoff Josef , Binot Elke , Merkelbach-Bruse Sabine , Fassunke Jana , Schulte Wolfgang , Ko Yon-Dschun , Schlesinger Andreas , Bos Marc , Gardizi Masyar , Engel-Riedel Walburga , Brockmann Michael , Serke Monika , Gerigk Ulrich , Hekmat Khosro , Frank Konrad F. , Reiser Marcel , Schulz Holger , Krüger Stefan , Stoelben Erich , Zander Thomas , Wolf Jürgen , Buettner Reinhard 
Published: December 2014

Abstract
Purpose: MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adeno- and squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer.
Experimental Design: We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-naïve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC.
Results: Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio ≥2.0 or average gene copy number per nucleus ≥6.0 or ≥10% of tumor cells containing ≥15 MET copies). The remaining cases can be subdivided into intermediate- (6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations.
Conclusion: MET amplification is not a mutually exclusive genetic event in therapy-naïve non–small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors. Clin Cancer Res; 21(4); 907–15. ©2014 AACR.
Integrative Analysis of Head and Neck Cancer Identifies Two Biologically Distinct HPV and Three Non-HPV Subtypes
Authors: Keck Michaela K. , Zuo Zhixiang , Khattri Arun , Stricker Thomas P. , Brown Christopher D. , Imanguli Matin , Rieke Damian , Endhardt Katharina , Fang Petra , Brägelmann Johannes , DeBoer Rebecca , El-Dinali Mohamed , Aktolga Serdal , Lei Zhengdeng , Tan Patrick , Rozen Steve G. , Salgia Ravi , Weichselbaum Ralph R. , Lingen Mark W. , Story Michael D. , Ang K. Kian , Cohen Ezra E.W. , White Kevin P. , Vokes Everett E. , Seiwert Tanguy Y. 
Published: December 2014

Abstract
Purpose: Current classification of head and neck squamous cell carcinomas (HNSCC) based on anatomic site and stage fails to capture biologic heterogeneity or adequately inform treatment.
Experimental Design: Here, we use gene expression-based consensus clustering, copy number profiling, and human papillomavirus (HPV) status on a clinically homogenous cohort of 134 locoregionally advanced HNSCCs with 44% HPV+ tumors together with additional cohorts, which in total comprise 938 tumors, to identify HNSCC subtypes and discover several subtype-specific, translationally relevant characteristics.
Results: We identified five subtypes of HNSCC, including two biologically distinct HPV subtypes. One HPV+ and one HPV− subtype show a prominent immune and mesenchymal phenotype. Prominent tumor infiltration with CD8+ lymphocytes characterizes this inflamed/mesenchymal subtype, independent of HPV status. Compared with other subtypes, the two HPV subtypes show low expression and no copy number events for EGFR/HER ligands. In contrast, the basal subtype is uniquely characterized by a prominent EGFR/HER signaling phenotype, negative HPV-status, as well as strong hypoxic differentiation not seen in other subtypes.
Conclusion: Our five-subtype classification provides a comprehensive overview of HPV+ as well as HPV− HNSCC biology with significant translational implications for biomarker development and personalized care for patients with HNSCC. Clin Cancer Res; 21(4); 870–81. ©2014 AACR.
Targeted Antioxidant Treatment Decreases Cardiac Alternans Associated With Chronic Myocardial Infarction
Authors: Plummer Bradley N. , Liu Haiyan , Wan Xiaoping , Deschênes Isabelle , Laurita Kenneth R. 
Published: December 2014

Background—

In myocardial infarction (MI), repolarization alternans is a potent arrhythmia substrate that has been linked to Ca
2+
cycling proteins, such as sarcoplasmic reticulum Ca
2+
ATPase (SERCA2a), located in the sarcoplasmic reticulum. MI is also associated with oxidative stress and increased xanthine oxidase (XO) activity, an important source of reactive oxygen species (ROS) in the sarcoplasmic reticulum that may reduce SERCA2a function. We hypothesize that in chronic MI, XO-mediated oxidation of SERCA2a is a mechanism of cardiac alternans.

Methods and Results—

Male Lewis rats underwent ligation of the left anterior descending coronary artery (n=54) or sham procedure (n=24). At 4 weeks, optical mapping of intracellular Ca
2+
and ROS was performed. ECG T-wave alternans (ECG ALT) and Ca
2+
transient alternans (Ca
2+
ALT) were induced by rapid pacing (300–120 ms) before and after the XO inhibitor allopurinol (ALLO, 50 µmol/L). In MI, ECG ALT (2.32±0.41%) and Ca
2+
ALT (22.3±4.5%) were significantly greater compared with sham (0.18±0.08%,
P
<0.001; 0.79±0.32%,
P
<0.01). Additionally, ROS was increased by 137% (
P
<0.01) and oxidation of SERCA2a by 30% (
P
<0.05) in MI compared with sham. Treatment with ALLO significantly decreased ECG ALT (−77±9%,
P
<0.05) and Ca
2+
ALT (−56±7%,
P
<0.05) and, importantly, reduced ROS (−65%,
P
<0.01) and oxidation of SERCA2a (−38%,
P
<0.05). CaMKII inhibition and general antioxidant treatment had no effect on ECG ALT and Ca
2+
ALT.

Conclusions—
These results demonstrate, for the first time, that in MI, increased ROS from XO is a significant cause of repolarization alternans. This suggests that targeting XO ROS production may be effective at preventing arrhythmia substrates in chronic MI.
Long-Term Effect of Fee-For-Service–Based Reimbursement Cuts on Processes and Outcomes of Care for Stroke
Authors: Tung Yu-Chi , Chang Guann-Ming , Cheng Shou-Hsia 
Published: December 2014

Background—
As healthcare spending continues to increase, reimbursement cuts have become 1 type of healthcare reform to contain costs. Little is known about the long-term impact of cuts in reimbursement, especially under a global budget cap with fee-for-service (FFS) reimbursement, on processes and outcomes of care. The FFS-based reimbursement cuts have been implemented since July 2002 in Taiwan. We examined the long-term association of FFS-based reimbursement cuts with trends in processes and outcomes of care for stroke.

Methods and Results—

We analyzed all 411 487 patients with stroke admitted to general acute care hospitals in Taiwan during the period 1997 to 2010 through Taiwan’s National Health Insurance Research Database. We used a quasi-experimental design with quarterly measures of healthcare utilization and outcomes and used segmented autoregressive integrated moving average models for the analysis. After accounting for secular trends and other confounders, the implementation of the FFS-based reimbursement cuts was associated with trend changes in computed tomography/magnetic resonance imaging scanning (0.31% per quarter;
P
=0.013), antiplatelet/anticoagulant use (−0.20% per quarter;
P
<0.001), statin use (0.18% per quarter;
P
=0.027), physiotherapy/occupational therapy assessment (0.25% per quarter;
P
<0.001), and 30-day mortality (0.06% per quarter;
P
<0.001).

Conclusions—
There are improvement trends in processes and outcomes of care over time. However, the reimbursement cuts from the FFS-based global budget cap are associated with trend changes in processes and outcomes of care for stroke. The FFS-based reimbursement cuts may have long-term positive and negative associations with stroke care.
Frontal Networks Associated With Command Following After Hemorrhagic Stroke
Authors: Mikell Charles B. , Banks Garrett P. , Frey Hans-Peter , Youngerman Brett E. , Nelp Taylor B. , Karas Patrick J. , Chan Andrew K. , Voss Henning U. , Connolly E. Sander , Claassen Jan 
Published: December 2014

Background and Purpose—
Level of consciousness is frequently assessed by command-following ability in the clinical setting. However, it is unclear what brain circuits are needed to follow commands. We sought to determine what networks differentiate command following from noncommand following patients after hemorrhagic stroke.

Methods—
Structural MRI, resting-state functional MRI, and electroencephalography were performed on 25 awake and unresponsive patients with acute intracerebral and subarachnoid hemorrhage. Structural injury was assessed via volumetric T1-weighted MRI analysis. Functional connectivity differences were analyzed against a template of standard resting-state networks. The default mode network (DMN) and the task-positive network were investigated using seed-based functional connectivity. Networks were interrogated by pairwise coherence of electroencephalograph leads in regions of interest defined by functional MRI.

Results—
Functional imaging of unresponsive patients identified significant differences in 6 of 16 standard resting-state networks. Significant voxels were found in premotor cortex, dorsal anterior cingulate gyrus, and supplementary motor area. Direct interrogation of the DMN and task-positive network revealed loss of connectivity between the DMN and the orbitofrontal cortex and new connections between the task-positive network and DMN. Coherence between electrodes corresponding to right executive network and visual networks was also decreased in unresponsive patients.

Conclusions—
Resting-state functional MRI and electroencephalography coherence data support a model in which multiple, chiefly frontal networks are required for command following. Loss of DMN anticorrelation with task-positive network may reflect a loss of inhibitory control of the DMN by motor-executive regions. Frontal networks should thus be a target for future investigations into the mechanism of responsiveness in the intensive care unit environment.
Physics of Changes in Synoptic Midlatitude Temperature Variability
Authors: Schneider Tapio , Bischoff Tobias , Płotka Hanna 
Published: December 2014

AbstractThis paper examines the physical processes controlling how synoptic midlatitude temperature variability near the surface changes with climate. Because synoptic temperature variability is primarily generated by advection, it can be related to mean potential temperature gradients and mixing lengths near the surface. Scaling arguments show that the reduction of meridional potential temperature gradients that accompanies polar amplification of global warming leads to a reduction of the synoptic temperature variance near the surface. This is confirmed in simulations of a wide range of climates with an idealized GCM. In comprehensive climate simulations (CMIP5), Arctic amplification of global warming similarly entails a large-scale reduction of the near-surface temperature variance in Northern Hemisphere midlatitudes, especially in winter. The probability density functions of synoptic near-surface temperature variations in midlatitudes are statistically indistinguishable from Gaussian, both in reanalysis data and in a range of climates simulated with idealized and comprehensive GCMs. This indicates that changes in mean values and variances suffice to account for changes even in extreme synoptic temperature variations. Taken together, the results indicate that Arctic amplification of global warming leads to even less frequent cold outbreaks in Northern Hemisphere winter than a shift toward a warmer mean climate implies by itself.