bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk of relapse phenotype recurrence in multiple sclerosis
Authors: Kalincik Tomas , Buzzard Katherine , Jokubaitis Vilija , Trojano Maria , Duquette Pierre , Izquierdo Guillermo , Girard Marc , Lugaresi Alessandra , Grammond Pierre , Grand’Maison Francois , Oreja-Guevara Celia , Boz Cavit , Hupperts Raymond , Petersen Thor , Giuliani Giorgio , Iuliano Gerardo , Lechner-Scott Jeannette , Barnett Michael , Bergamaschi Roberto , Van Pesch Vincent , Amato Maria Pia , van Munster Erik , Fernandez-Bolanos Ricardo , Verheul Freek , Fiol Marcela , Cristiano Edgardo , Slee Mark , Rio Maria Edite , Spitaleri Daniele , Alroughani Raed , Gray Orla , Saladino Maria Laura , Flechter Sholmo , Herbert Joseph , Cabrera-Gomez Jose Antonio , Vella Norbert , Paine Mark , Shaw Cameron , Moore Fraser , Vucic Steve , Savino Aldo , Singhal Bhim , Petkovska-Boskova Tatjana , Parratt John , Sirbu Carmen-Adella , Rozsa Csilla , Liew Danny , Butzkueven Helmut ,   on behalf of the MSBase Study Group
Published: April 2014

Objectives:

The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype.

Methods:

Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis.

Results:

Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8–5, p = 10-14). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease.

Conclusion:

Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.
Looking age-appropriate while growing old gracefully: A qualitative study of ageing and body image among older adults
Authors: Jankowski Glen S , Diedrichs Phillippa C , Williamson Heidi , Christopher Gary , Harcourt Diana
Published: April 2014

Body dissatisfaction can be significantly detrimental to wellbeing. Little is known about older adults’ body image, despite the fact that ageing causes unique bodily changes and that sociocultural pressures to resist these changes abound. We conducted six focus groups with a UK community sample of White British and South Asian older adults aged 65–92 years. Thematic analysis highlighted four themes: appearance indicates capability and identity; physical ability trumps appearance; felt pressures to age ‘gracefully’ while resisting appearance changes; and gender and cultural differences. These findings suggest that older adults’ body image can have important implications for their wellbeing and merits researchers’ attention.
Visual criminology and carceral studies: Counter-images in the carceral age
Authors: Brown Michelle
Published: April 2014

Mass incarceration maps onto global neoliberal carceral formations that, in turn, look very much like a visual iconography of social suffering. Camp or prison-like conditions define the daily life of many of the world’s inhabitants caught in contexts of detention, incarceration, forced migration, and population displacement. Often depicted as abject subjects, actors in carceral contexts and the people who organize with them seek to find strategies of representation that humanize and politicize their existence. This essay attempts to gain a sense of the visual struggles at the heart of these carceral scenes by way of an analysis of the use of images and new media by current and former prisoners, community members, artists, and scholars to counter mass incarceration in the United States. Such scenes are significant sites for examining how a visual criminology might reveal and participate in the contestations and interventions that increasingly challenge the project of mass incarceration.
(Un)seeing like a prison: Counter-visual ethnography of the carceral state
Authors: Schept Judah
Published: April 2014

While prisons proliferate in the rural landscape and sites of penal tourism expand, the carceral state structures the available visual and analytic vantages through which to perceive this growing visibility. Using examples from fieldwork in Kentucky, including Appalachian prison communities and a site of penal tourism, this article proposes ‘counter-visual’ ethnography to better perceive the ideological work that the carceral state performs in the spatial and cultural landscape. A counter-visual ethnography retrains our eyes to see that which is not ‘there’ but which structures the contemporary empirical realities we observe, record, and analyze: the ghosts of racialized regimes past, the sediment of dirty industry that seeps into and imbues the present, and the trans-historical and trans-local circulation of carceral logics and epistemologies. In addition, this article suggests the important role images play in shaping alternative vantages from which to better perceive the carceral state with historical, spatial, and political acuity.
From object to encounter: Aesthetic politics and visual criminology
Authors: Young Alison
Published: April 2014

Recent criminological research has engaged with images of crime such that there increasingly appears to exist a need for a specifically visual criminology. Within visual criminology, however, images are frequently constructed as objects of analysis rather than as constitutive elements of the discursive field. This article draws upon the specific context of the social, cultural and legal responses to uncommissioned words and images in public space—street art and graffiti writing. Focusing on one instance of unauthorized image making, I argue for the dynamic role of the image in the constitution of crime in contemporary society and culture, thanks to the affective dimension of the encounter between spectator and image. The complex range of responses to street art and graffiti highlights ways in which visual criminology must ensure that it eschews an object-centred approach to the image, and conceptualize it instead by means of an aesthetic politics of the encounter.
Rethinking political participation: A pedagogical approach for citizenship education
Authors: Expósito Leonel Pérez
Published: April 2014

A significant body of literature on citizenship education and youth participation has progressively replaced political participation with other categories such as citizenship participation, community involvement or civic engagement. The demotion of political participation is also characteristic of different programmes of citizenship education embracing the same dominant categories. The article argues that this tendency reveals a depoliticised approach to citizenship education, which emphasises an apolitical view on adolescents’ participation and, consequently, a conception of students as depoliticised subjects. The depoliticisation of citizenship education risks theoretical transparency in regard to the kind of participation it aims to promote and, therefore, jeopardises citizenship education’s pedagogical efficacy. Drawing on political theory and philosophy, political science and sociological theory, the article analyses the scope and potential of the notion of political participation in order to develop an approach that is inclusive of adolescents, based on the development of their own politicity and especially thought for being enacted in the school as a central component of citizenship education.
Review of Survey and Experimental Research That Examines the Relationship Between Alcohol Consumption and Men’s Sexual Aggression Perpetration
Authors: Abbey Antonia , Wegner Rhiana , Woerner Jacqueline , Pegram Sheri E. , Pierce Jennifer
Published: April 2014

This article systematically reviews empirical studies that examine associations between alcohol consumption and men’s sexual aggression with the goal of identifying major findings; gaps in current knowledge; and directions for future research, practice, and policy. We identified 25 cross-sectional surveys, 6 prospective studies, and 12 alcohol administration experiments published between 1993 and August 2013 with male college students and young adult (nonincarcerated) samples. Many cross-sectional surveys have demonstrated that distal and proximal measures of men’s alcohol consumption are positively associated with sexual assault perpetration, although very few of these studies evaluated how alcohol interacts with other risk and protective factors to exacerbate or inhibit sexual aggression. There are surprisingly few surveys that examine alcohol’s effects at the event level and over short-time intervals to identify how changes in alcohol consumption are associated with changes in perpetration status. Alcohol administration studies suggest some important mechanisms that warrant additional investigation.
Campus Sexual Misconduct
Authors: Koss Mary P. , Wilgus Jay K. , Williamsen Kaaren M.
Published: April 2014

Campus response to sexual violence is increasingly governed by federal law and administrative guidance such as the 1972 Title IX, the 2011 Dear Colleague Letter (DCL), and the 2013 Violence Against Women Act. Educational institutions are directed to expand disciplinary responses and establish coordinated action to eliminate sexual violence and remedy its effects. Compliance fosters a quasi-criminal justice approach not suited to all sexual misconduct and inconsistent with developing practice in student conduct management. This article envisions restorative justice (RJ) enhancements to traditional student conduct processes that maintain compliance, expand options, empower victim choice, and increase responsiveness to DCL aims. The article (1) defines sexual violence and sexual harassment within the DCL scope, (2) elaborates the DCL position on permissible alternative resolutions and differentiates mediation from RJ, (3) sequences action steps from case report to finalization, including both restorative and traditional justice pathways; and (4) discusses building support for innovation beginning with existing campus response.
When the Medium Becomes “Well Done”
Authors: Galily Yair
Published: April 2014

One of the fundamental issues in the relation between television and sports has been the transference from watching a game or a sport in the field (the stadium) to the viewing experience through a proxy (the medium). The present article argues that sport broadcasts on television in the twenty-first century do not merely provide a sophisticated view of what takes place at the stadium but a new creation with unique characteristics. By using the latest technology-driven examples and assuming that other ones are already being used such as the “second screen” combination of watching TV and simultaneously using a smartphone or tablet for better statistics or social interaction, it is asserted that “being there” has become less imperative, as alternatives to watching matches live and in person at many sporting events have become in many cases better options.
A Comparison of Covert and Videotape Modeling Strategies for Training Complex Mechanical Assembly Tasks
Authors: Linnerooth Peter J. N. , Houlihan Daniel , Lenz Melissa A. , Buchanan Jeffrey
Published: April 2014

Experimentation was conducted comparing videotape self-modeling and videotape peer/other modeling to self-directed mental rehearsal (a covert modeling procedure) and a no-training (physical practice) control condition in training a mechanical device assembly task. Eighty male and female college students were introduced to the assembly task in a timed pretest trial and then videotaped performing the assembly task in a second trial. Over the next 4 days, subjects were randomly assigned to training conditions and repeatedly trained and tested in the mechanical device assembly task. The effects of training methods upon assembly times, self-efficacy expectations regarding assembly task performance, and subjective impressions of the nature and usefulness of training were examined. Superior assembly performance over initial training and at 4 months post-training follow-up was observed for the self-directed mental rehearsal training condition and discussed.
Effects of music relaxation video on pain and anxiety for women with gynaecological cancer receiving intracavitary brachytherapy: a randomised controlled trial
Authors: Chu-Hui-Lin Chi Grace , Young Anne , McFarlane Judith , Watson Mary , Coleman Robert L , Eifel Patricia J , LoBiondo-Wood Geri , Bodurka Diane C , Richardson Michael
Published: April 2014

The purpose of this study was to explore the effects of music relaxation video on pain severity, opioid utilisation, and anxiety experienced by women with gynaecological cancer undergoing intracavitary brachytherapy. A two-group randomised controlled trial was conducted in an academic comprehensive cancer centre. Sixty women were randomly assigned to either an experimental group ( n = 31) that watched a 30-minute music relaxation video four times (total 120 minutes) or a control group ( n = 29) that received standard nursing care during the first 44 hours of the intracavitary brachytherapy. Data were collected to evaluate the effects on pain severity, opioid utilisation and anxiety between groups. Pain scores were measured before and after patients watched the 30-minute music relaxation video and anxiety scores were measured following the video. The amount of opioid consumption was recorded during the 44-hour treatment. Data were tested using ANOVA and t-test. Perceived pain reduction was statistically significant in the experimental group ( p = 0.027), but this did not translate into lower total consumption of opioids between the two study groups. Anxiety level reduction was statistically significant in the experimental group ( p = 0.001). Music relaxation videos hold promise to be used in conjunction with standard pharmacologic therapy to reduce perceived pain and anxiety levels during the treatments.
Influence of irradiation temperature on microstructure of EU batch of ODS Eurofer97 steel irradiated with neutrons
Authors: Kolluri M. , Edmondson P. D. , Luzginova N. V. , Berg F. A. v. d.
Published: April 2014

A TEM investigation of an EU batch of oxide dispersed strengthened (ODS) Eurofer97 steel specimens, irradiated to 1 and 3 dpa at 300, 450 and 550°C in high flux reactor at Petten, has been performed to understand the influence of irradiation temperature on the characteristics of irradiation defects and, eventually, on the resulting mechanical properties of this material. Specimens irradiated at 300°C revealed the presence of a high density of black dot damage and small self-interstitial atom (SIA) dislocation loops causing substantial hardening and embrittlement. In contrast, negligible black dot damage, low density of large SIA loops and networks of dislocations are observed in specimens irradiated at 450 and 550°C. The lath martensitic structure and ODS particles remain unaffected after irradiation in all specimens. These results are discussed in view of possible activation of defect annihilation mechanisms to explain the observed recovery of mechanical properties at high irradiation temperatures.
Critical Assessment 2: Hydrogen induced fracture in austenitic, high-manganese TWIP steel
Authors: Suh Dong-Woo
Published: April 2014

Austenitic steels containing large manganese concentrations, that deform by mechanical twinning and dislocation slip, have attractive mechanical properties. They are often known as TWIP steels because the work hardening rate is enhanced by twinning, thus permitting large elongations before the onset of plastic instabilities. However, some such steels suffer from hydrogen-induced fracture. This susceptibility can be relieved by adding aluminium, although the mechanism by which aluminium acts remains a matter of discussion. The various proposed mechanisms and data from the literature are critically assessed, and some indications given on fruitful paths for progress.
Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study
Authors: Chee Cheng E. , Ashrani Aneel A. , Marks Randolph S. , Petterson Tanya M. , Bailey Kent R. , Melton L. Joseph , Heit John A.
Published: April 2014

Key Points

VTE recurrence risk in patients with cancer can be stratified by cancer type, stage, stage progression, and presence of leg paresis. Patients with cancer at high VTE recurrence risk should be considered for secondary prophylaxis.
OKT3 prevents xenogeneic GVHD and allows reliable xenograft initiation from unfractionated human hematopoietic tissues
Authors: Wunderlich Mark , Brooks Ryan A. , Panchal Rushi , Rhyasen Garrett W. , Danet-Desnoyers Gwenn , Mulloy James C.
Published: April 2014

Key Points

Ex vivo addition of OKT3 is an economical and easy method to prevent xenogeneic GVHD and rescue patient leukemia sample xenografts. OKT3-treated whole UCB produces robust, durable hematopoietic xenografts that are indistinguishable from CD34+ grafts.
The safety and usefulness of neutron brachytherapy and external beam radiation in the treatment of patients with gastroesophageal junction adenocarcinoma with or without chemotherapy
Authors: Wang Qifeng , Li Tao , Liu Huiming , Jia Xitang , Liu Bo , Wan Xin , Lang Jinyi
Published: April 2014

Purpose

To assess the safety and usefulness of neutron brachytherapy (NBT) as an adjuvant in the treatment of patients with gastroesophageal junction adenocarcinoma (GEJAC) with external beam radiation (EBRT), with or without chemotherapy.

Methods and Materials

In total, 197 patients with localized, advanced GEJAC received EBRT and NBT with or without chemotherapy. Radiotherapy consisted of external irradiation to a total dose of 40–54 Gy (median 50 Gy) and brachytherapy to 8–25 Gy (median 20 Gy) in two to five fractions. In total, 88 patients received chemotherapy that consisted of two cycles of a regimen with CDDP and 5FU from days l-4. The cycles were administered on days 1 and 29. MMC was given alone in bolus injection on day 1 each week. The cycles were administered on days 1, 8, 15 and 22.

Results

The duration of follow-up ranged from six to 106 months (median 30.4 months). The median survival time for the 197 patients was 13.3 months, and the one, two, three- and five-year rates for overall survival were 57.1%, 35.1%, 23.0% and 9.2%, respectively. For acute toxicity, no incidences of fistula and massive bleeding were observed during this treatment period. In total, 159 (80.7%) patients developed Grade 2 hematologic toxicity and 146 (74.1%) patients developed Grade ≥ 2 esophagitis. The median times of incidence of fistula and bleeding were 9.5 (3–27.3) months and 12.7 (5–43.4) months, respectively. The incidence of severe, late complications was related to higher NBT dose/f (20–25 Gy/5 F) and higher total dose(≥70 Gy). In total, 75.2% of the patients resumed normal swallowing and 2.0% had some residual dysphagia (non-malignant) requiring intermittent dilatation.

Conclusion

A combination of EBRT and NBT with the balloon type applicator was feasible and well tolerated. Better local-regional control and overall survival cannot achieved by a higher dose, and in contrast, a higher dose caused more severe esophageal injury.
Advancing quantitative description of porosity in autogenous laser-welds of 304L stainless steel
Authors: Madison Jonathan D , Aagesen Larry K , Chan Victor WL , Thornton Katsuyo
Published: April 2014

Porosity in linear autogenous laser welds of 304L stainless steel has been investigated using micro-computed tomography to reveal defect content in fifty-four welds made with varying delivered power, travel speed and focal lens. Trends associated with porosity size and frequencies are shown and interfacial measures are employed to provide quantitative descriptors of pore shape, directionality, interspacing and solid linear fraction. Lastly, the coefficient of variation associated with equivalent pore radii is reported toward a discussion of microstructural variability and the influence of process-parameters on such variability.
Genetic variant in IL33 is associated with susceptibility to rheumatoid arthritis
Authors: Li Chun , Mu Rong , Guo Jianping , Wu Xinyu , Tu Xin , Liu Xu , Hu Fanlei , Guo Shiwei , Zhu Jiaxin , Xu Huji , Li Zhanguo
Published: April 2014

Introduction

Interleukin (IL)-33 is a proinflammatory cytokine contributing to the pathogenesis of rheumatoid arthritis (RA). The gene encoding IL-33 may serve as a genetic factor and be associated with the risk of RA. To investigate the potential association between IL33 and RA, we performed a case–control study based on Chinese Han population.

Methods

A three-stage case–control study was performed. Two tag single-nucleotide polymorphisms (SNPs) (rs7044343 and rs10975514), mapping to the IL33 gene, were first genotyped in the discovery population. We further genotyped rs7044343 and rs10975514 in the validation and replication population. The associations between the two tag SNPs and phenotypic subgroups of RA and levels of serum IL-33 were assessed with a logistic regression model.

Results

In the discovery population, the CC genotype of rs7044343 was associated with RA patients (odds ratio (OR) = 0.777, 95% confidence interval (CI), 0.611 to 0.988; P = 0.040). After anti-citrullinated peptide antibody (ACPA) stratification, the CC genotype of rs7044343 was also shown to be a protective genotype in RA without ACPA (OR = 0.610; 95% CI, 0.379 to 0.982; P = 0.042). In the validation population and replication population, the association between rs7044343 and RA, especially ACPA-negative RA, was still significant. A meta-analysis of discovery, validation, and replication panels confirmed the association between CC genotype of rs7044343 and RA (Pcombined = 0.0004; ORcombined = 0.77; 95% CI, 0.67 to 0.89). No evidence was found for heterogeneity between three sample sets (P
het
 = 0.99; I2 = 0%). Similar results were also obtained in ACPA-negative RA (Pcombined = 0.0002; ORcombined = 0.57; 95% CI, 0.43 to 0.77). No association was detected between rs10975514 polymorphism and RA susceptibility in the discovery and validation population. The serum levels of IL-33 were significantly lower in the patients with the rs7044343 CC genotype.

Conclusion

The CC genotype of rs7044343 in IL33 is associated with RA patients and downregulates IL-33 expression in RA.
Effect of intensive care after cardiac arrest on patient outcome: a database analysis
Authors: Schober Andreas , Holzer Michael , Hochrieser Helene , Posch Martin , Schmutz Rene , Metnitz Philipp
Published: April 2014

Introduction

The study aimed to determine the impact of treatment frequency, hospital size, and capability on mortality of patients admitted after cardiac arrest for postresuscitation care to different intensive care units.

Methods

Prospectively recorded data from 242,588 adults consecutively admitted to 87 Austrian intensive care units over a period of 13 years (1998 to 2010) were analyzed retrospectively. Multivariate analysis was used to assess the effect of the frequency of postresuscitation care on mortality, correcting for baseline parameters, severity of illness, hospital size, and capability to perform coronary angiography and intervention.

Results

In total, 5,857 patients had had cardiac arrest and were admitted to an intensive care unit. Observed hospital mortality was 56% in the cardiac-arrest cohort (3,302 nonsurvivors). Patients treated in intensive care units with a high frequency of postresuscitation care generally had high severity of illness (median Simplified Acute Physiology Score (SAPS II), 65). Intensive care units with a higher frequency of care showed improved risk-adjusted mortality. The SAPS II adjusted, observed-to-expected mortality ratios (O/E-Ratios) in the three strata (<18; 18 to 26; >26 resuscitations per ICU per year) were 0.869 (95% confidence interval, 0.844 to 894), 0.876 (0.850 to 0.902), and 0.808 (0.784 to 0.833).

Conclusions

In this database analysis, a high frequency of post-cardiac arrest care at an intensive care unit seemed to be associated with improved outcome of cardiac-arrest patients. We were able to identify patients who seemed to profit more from high frequency of care, namely, those with an intermediate severity of illness. Considering these findings, cardiac-arrest care centers might be a reasonable step to improve outcome in this specific population of cardiac-arrest patients.
Management of Pseudomonas aeruginosa pneumonia: one size does not fit all
Authors: Rello Jordi , Borgatta Bárbara , Lagunes Leonel
Published: April 2014

In view of the mortality associated with Pseudomonas aeruginosa (PSA) ventilator-associated pneumonia (VAP) and the frequency of inadequate initial empiric therapy, recent findings underscore the need for a different management paradigm with effective anti-pseudomonal vaccines for prophylaxis of patients at risk. The association of virulence factors is a variable that splits PSA in two phenotypes, with the possibility of adjunctive immunomodulatory therapy for management of virulent strains. We comment on recent advances in and the state of the art of PSA-VAP management and discuss a new paradigm for tailored and optimal management.
Discovering the complexity of the metazoan transcriptome
Authors: Hangauer Matthew J , Carpenter Susan , McManus Michael T
Published: April 2014

Recent studies harnessing deep RNA sequencing coupled with other complementary data have revealed the complex nature of metazoan transcriptomes.
A genome scale overexpression screen to reveal drug activity in human cells
Authors: Arnoldo Anthony , Kittanakom Saranya , Heisler Lawrence E , Mak Anthony B , Shukalyuk Andrey I , Torti Dax , Moffat Jason , Giaever Guri , Nislow Corey
Published: April 2014

Target identification is a critical step in the lengthy and expensive process of drug development. Here, we describe a genome-wide screening platform that uses systematic overexpression of pooled human ORFs to understand drug mode-of-action and resistance mechanisms. We first calibrated our screen with the well-characterized drug methotrexate. We then identified new genes involved in the bioactivity of diverse drugs including antineoplastic agents and biologically active molecules. Finally, we focused on the transcription factor RHOXF2 whose overexpression conferred resistance to DNA damaging agents. This approach represents an orthogonal method for functional screening and, to our knowledge, has never been reported before.
Data from the Network for Earthquake Engineering Simulation/E-Defense Collaborative Test Program on Innovative Isolation Systems and Nonstructural Components
Authors: Guzman Jean , Ryan Keri L.
Published: April 2014

The data sets generated from E-Defense shake table experiments of a full-scale, five-story building tested with two innovative isolation systems and in the fixed-base configuration are available in the Network for Earthquake Engineering Simulation (NEES) Project Warehouse. The experiments included an integrated subassemblage of partition walls, suspended ceilings, and sprinkler piping on the fourth and fifth floors of the building; a full-story precast concrete cladding column cover; and enclosed areas staged with building contents. Totaling approximately 211 GB between three experiments, the data set includes isolator forces and displacements, floor accelerations, and story drifts, local accelerations, and relative displacements at strategic locations on the nonstructural components, as well as extensive videos and inspection photos. The project was a collaboration between U.S. researchers of the NEES Tools for Isolation and Protective Systems (TIPS) and NEES Nonstructural Grand Challenge projects and Japanese researchers from the National Research Institute of Earth Science and Disaster Prevention. Data set DOIs are 10.4231/D3X34MR7R, 10.4231/D3SB3WZ43, and 10.4231/D3NP1WJ3P.
Bruton's Tyrosine Kinase: From X-Linked Agammaglobulinemia Toward Targeted Therapy for B-Cell Malignancies
Authors: Ponader Sabine , Burger Jan A.
Published: April 2014

Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy.
Modafinil for the Treatment of Fatigue in Lung Cancer: Results of a Placebo-Controlled, Double-Blind, Randomized Trial
Authors: Spathis Anna , Fife Kate , Blackhall Fiona , Dutton Susan , Bahadori Ronja , Wharton Rose , O'Brien Mary , Stone Patrick , Benepal Tim , Bates Nick , Wee Bee
Published: April 2014

Purpose

Fatigue is a distressing symptom occurring in more than 60% of patients with cancer. The CNS stimulants modafinil and methylphenidate are recommended for the treatment of cancer-related fatigue, despite a limited evidence base. We aimed to evaluate the efficacy and tolerability of modafinil in the management of fatigue in patients with non–small-cell lung cancer (NSCLC).

Patients and Methods

Adults with advanced NSCLC and performance status of 0 to 2, who were not treated with chemotherapy or radiotherapy within the last 4 weeks, were randomly assigned to daily modafinil (100 mg on days 1 to 14; 200 mg on days 15 to 28) or matched placebo. The primary outcome was change in Functional Assessment of Chronic Illness Therapy (FACIT) –Fatigue score from baseline to 28 days, adjusted for baseline fatigue and performance status. Secondary outcomes included safety and patient-reported measures of depression, daytime sleepiness, and quality of life.

Results

A total of 208 patients were randomly assigned, and 160 patients (modafinil, n = 75; placebo, n = 85) completed questionnaires at both baseline and day 28 and were included in the modified intention-to-treat analysis. FACIT-Fatigue scores improved from baseline to day 28 (mean score change: modafinil, 5.29; 95% CI, 2.57 to 8.02; placebo, 5.09; 95% CI, 2.54 to 7.65), but there was no difference between treatments (0.20; 95% CI, −3.56 to 3.97). There was also no difference between treatments for the secondary outcomes; 47% of the modafinil group and 23% of the placebo group stated that the intervention was not helpful.

Conclusion

Modafinil had no effect on cancer-related fatigue and should not be prescribed outside a clinical trial setting. Its use was associated with a clinically significant placebo effect.
Oral Human Papillomavirus (HPV) Infection in HPV-Positive Patients With Oropharyngeal Cancer and Their Partners
Authors: D'Souza Gypsyamber , Gross Neil D. , Pai Sara I. , Haddad Robert , Anderson Karen S. , Rajan Shirani , Gerber Jennifer , Gillison Maura L. , Posner Marshall R.
Published: April 2014

Purpose

To better understand oral human papillomavirus (HPV) infection and cancer risk among long-term sexual partners of patients with HPV-positive oropharyngeal cancer (HPV-OPC).

Patients and Methods

An oral rinse sample, risk factor survey, cancer history, and oral examination (partners only) were collected from patients with HPV-OPC and their partners. Oral rinse samples were evaluated for 36 types of HPV DNA using PGMY 09/11 primers and line-blot hybridization and HPV16 copy number using quantitative polymerase chain reaction. Oral HPV prevalence was compared with infection among those age 45 to 65 years using National Health and Nutrition Examination Survey (NHANES) 2009-2010.

Results

A total of 164 patients with HPV-OPC and 93 of their partners were enrolled. Patients were primarily men (90%), were never-smokers (51%), and had performed oral sex (97%), with a median age of 56 years; they had a high prevalence of oncogenic oral HPV DNA (61%) and oral HPV16 DNA (54%) at enrollment. Female partners had comparable oncogenic oral HPV prevalence compared with members of the general population of the same age (1.2% v 1.3%). Among the six male partners, no oncogenic oral HPV infections were detected. No precancers or cancers were identified during partner oral cancer screening examinations. However, a history of cervical disease was reported by nine partners (10.3%) and two female patients (11.8%), and three patients (2.0%) reported a previous partner who developed invasive cervical cancer.

Conclusion

Oral HPV16 DNA is commonly detected among patients with HPV-OPC at diagnosis, but not among their partners. Partners of patients with HPV-OPC do not seem to have elevated oral HPV infection compared with the general population.
Blunted Day-Night Changes in Luteinizing Hormone Pulse Frequency in Girls With Obesity: the Potential Role of Hyperandrogenemia
Authors: Collins Jessicah S. , Beller Jennifer P. , Burt Solorzano Christine , Patrie James T. , Chang R. Jeffrey , Marshall John C. , McCartney Christopher R.
Published: April 2014

Context:

Puberty is marked by sleep-associated changes in LH pulse frequency and amplitude. Early pubertal girls with obesity exhibit blunted day-to-night changes in LH secretion; whether this occurs in late pubertal obese girls is unknown.

Objective:

The objective of the study was to test two hypotheses: 1) blunted day-to-night changes in LH secretion occur in both early and late pubertal obese girls, and 2) such alterations are specifically associated with hyperandrogenemia.

Design:

This was a cross-sectional analysis.

Setting:

The study was conducted at a clinical research center.

Patients or Other Participants:

Twenty-seven early pubertal, premenarcheal girls (12 of whom were obese) and 63 late pubertal (postmenarcheal) girls (27 of whom were obese) participated in the study.

Intervention:

Blood samples were taken every 10 minutes from 7:00 pm to 7:00 am.

Main Outcome Measure:

Change in LH pulse frequency [LH interpulse interval (IPI)] from daytime hours (7:00 pm-11:00 pm, while awake) to nighttime hours (11:00 pm to 7:00 am, while generally asleep).

Results:

Both nonobese and obese postmenarcheal girls demonstrated significant day-to-night decreases in LH pulse frequency (IPI increases of 33% and 16%, respectively), but day-to-night changes were blunted in obese girls (P = .004, obese vs nonobese). Day-to-night LH pulse frequency decreased significantly in postmenarcheal obese subjects with normal T concentrations (26% IPI increase) but not in those with hyperandrogenemia. Similar differences were evident for LH pulse amplitude. Nonobese and obese early pubertal girls exhibited nonsignificant differences in day-night LH pulse frequency (day to night IPI increase of 26% vs decrease of 1%, respectively).

Conclusions:

Day-to-night changes in LH pulse secretion are blunted in postmenarcheal obese adolescent girls. This phenomenon may in part reflect hyperandrogenemia.
An Independent Study of a Gene Expression Classifier (Afirma) in the Evaluation of Cytologically Indeterminate Thyroid Nodules
Authors: McIver Bryan , Castro M. Regina , Morris John C. , Bernet Victor , Smallridge Robert , Henry Michael , Kosok Laura , Reddi Honey
Published: April 2014

Context:

Molecular markers hold the promise of improved diagnostic yield in thyroid fine-needle biopsy. The Afirma gene expression classifier (GEC), available commercially, reports a negative predictive value of 94% in the diagnosis of benign nodules after indeterminate cytology. However, there are currently no independent studies of the performance of this assay.

Objective:

The aim was to assess the performance of the Afirma GEC in an academic medical center.

Design:

Samples for the GEC were collected according to the manufacturer's recommended protocol from patients undergoing thyroid fine-needle aspiration. We requested GEC analysis on nodules reported cytologically as follicular neoplasm or atypia or follicular lesion of undetermined significance from patients willing to defer surgery.

Patients:

All patients undergoing thyroid fine-needle aspiration during the study period, whose cytology was reported as follicular neoplasm or atypia of undetermined significance/follicular lesion of undetermined significance, were offered access to the test and recruited to this study.

Intervention:

Patients whose GEC was “benign” were offered ultrasound follow-up in lieu of surgery. Those with a “suspicious” GEC were advised to undergo diagnostic lobectomy.

Setting:

The study was conducted at a large academic medical center.

Main Outcome Measure:

We measured the rate of benign and suspicious calls from the Afirma GEC and histological diagnosis after surgery.

Results:

A total of 72 nucleic acid samples were sent for GEC analysis. In 12 (17%) of these samples, there was insufficient mRNA, leaving 60 Afirma results for analysis. Of these, 16 (27%) were benign, whereas 44 (73%) were suspicious. The rate of confirmed malignancy in GEC-suspicious nodules was only 17%.

Conclusion:

The Afirma GEC demonstrates a lower than expected rate of benign reports in follicular or Hürthle cell neoplasm and a lower than anticipated malignancy rate within GEC-suspicious nodules. These data suggest that the positive predictive value of the GEC is lower than previously reported and call into question the performance of the test when applied in the context of specialized academic cytopathology.
The Performance of Cajun English in Boudreaux and Thibodeaux Jokes
Authors: Carmichael Katie
Published: April 2014

In South Louisiana, there is a genre of jokes featuring the bumbling Cajun characters Boudreaux and Thibodeaux. These jokes are often told with an exaggerated Cajun English accent, an ideal opportunity to examine and better understand local perceptions of Cajun English linguistic features. Th-stopping, nonaspiration of [p, t, k], and vowel quality were analyzed in recordings of six Lafourche Parish, Louisiana speakers conversing casually as well as performing Boudreaux and Thibodeaux jokes. While all speakers exaggerated one or the other consonantal feature while joketelling, vowel quality was not manipulated in the expected ways. Such patterning may indicate that th-stopping and nonaspiration of [p, t, k] are more salient, or more easily imitable, features of Cajun English than the vowel features examined. Notably, there was some patterning of features exaggerated based on where the speaker lived along the bayou, with “up the bayou” joketellers having a more standard baseline to begin with and thus exaggerating different features, demonstrating the importance of considering culturally specific social categories in analyzing performances of local speech varieties.
The Consequences of Bouvines
Authors: Baldwin John W. , Simons Walter
Published: April 2014

On the occasion of the eight hundredth anniversary of the Battle of Bouvines (July 27, 1214), this essay examines its significance for the Capetian monarchy and its impact inside and outside the French kingdom. It argues that Philip II Augustus’s victory safeguarded the administrative reforms he had undertaken since 1190, boosted royal ideology, extended royal control in northwestern and central parts of France at the expense of Anglo-Angevin claims, cleared the path for the Albigensian crusade in the south, and eliminated Flemish and German threats from the north and east; the battle’s ramifications for internal English, Flemish, and German affairs were far-reaching. The battle thus secured Capetian supremacy in France throughout the thirteenth century, but at the turn of the fourteenth Flanders and Gascony again posed intractable problems.

Le 800ème anniversaire de la bataille de Bouvines (27 juillet 1214) nous offre l’occasion de réévaluer ses effets sur la monarchie capétienne, le royaume de France et l’Europe. Cet essai soutient que la victoire du roi Philippe Auguste consolida les réformes administratives initiées depuis 1190, renforça l’idéologie royale, imposa l’autorité royale dans les territoires angevins du nord-ouest et au centre de la France, ouvrit la voie à la croisade albigeoise dans le Midi et élimina les menaces flamandes et allemandes dans le nord et l’est; en fait, la bataille eut d’importantes conséquences pour les affaires intérieures de l’Angleterre, de la Flandre et de l’Empire. En somme, Bouvines assura la suprématie des Capétiens tout au long du treizième siècle, mais au début du quatorzième siècle les problèmes épineux que constituaient la Flandre et la Guyenne s’imposèrent de nouveau.
Imagining the Trans-Mediterranean Republic: Algeria, Republicanism, and the Ideological Origins of the French Imperial Nation-State, 1848-1870
Authors: Murray-Miller Gavin
Published: April 2014

This article looks at the dialogue between metropolitan political elites and Algerian activists that grew up during the Second Empire, revisiting an important moment in the making of France’s “modern” republican democracy. Through an examination of Algerian newspapers and publications, it assesses the role that colonial public opinion played in the “republican renaissance” of the 1860s, detailing how colon polemicists consciously tailored an ideology of moderate republicanism to fit colonial society and elaborate a brand of republican colonialism that would, in time, provide the ideological basis for the colonial republic. In placing nineteenth-century French political history in a trans-Mediterranean framework, this article challenges the customary history of hexagonal France, indicating the vital role colonial activists played in the making of republican colonialism, influencing considerations of the French nation and citizenship that would, in time, encourage the conception of a French imperial nation-state supported under the Third Republic.

Le dialogue entre les élites politiques métropolitaines et les colons algériens jouait un rôle important dans la réalisation de la démocratie républicaine moderne française pendant le Second Empire. A travers sa lecture de divers journaux algériens, cet article met en lumière le rapport entre l’opinion publique coloniale et la « renaissance républicaine » des années 1860, ainsi que les moyens que les colons ont utilisés pour formuler une idéologie républicaine qui s’appliquait à la société coloniale. Cette idéologie allait jeter les bases de la république coloniale. En concevant l’histoire politique française dans une optique transméditerranéenne, l’article conteste l’histoire conventionnelle de la France hexagonale et révèle la contribution des activistes algériens français à l’édification du colonialisme républicain et aux conceptions de la nationalité et de la citoyenneté essentielles à la formation de la nation impériale française sous la Troisième République.
Mitochondrial fission is required for cardiomyocyte hypertrophy via a Ca2+-calcineurin signalling pathway
Authors: Pennanen Christian , Parra Valentina , López-Crisosto Camila , Morales Pablo E. , del Campo Andrea , Gutierrez Tomás , Rivera-Mejías Pablo , Kuzmicic Jovan , Chiong Mario , Zorzano Antonio , Rothermel Beverly A. , Lavandero Sergio
Published: April 2014

Cardiomyocyte hypertrophy has been associated with diminished mitochondrial metabolism. Mitochondria are crucial organelles for the production of ATP, whose morphology and function are regulated by the dynamic processes of fusion and fission. The relationship between mitochondrial dynamics and cardiomyocyte hypertrophy is still poorly understood. Here, we show that treatment of cultured neonatal rat cardiomyocytes with the hypertrophic agonist norepinephrine (NE) promotes mitochondrial fission (characterized by a decrease in mitochondrial mean volume and an increase in the relative number of mitochondria per cell) and a decrease in mitochondrial function. We demonstrate that NE acts via α1-adrenergic receptors to increase cytoplasmic Ca2+, activating calcineurin and promoting migration of the fission protein Drp1 to mitochondria. Dominant negative Drp1 (K38A) not only prevented mitochondrial fission, it also blocked hypertrophic growth of cardiomyocytes in response to NE. Remarkably, an antisense adenovirus against the fusion protein Mfn2 (AsMfn2) was sufficient to increase mitochondrial fission and stimulate a hypertrophic response without agonist treatment. Collectively, these results demonstrate the importance of mitochondrial dynamics in the development of cardiomyocyte hypertrophy and metabolic remodelling.
Expression of endoglin isoforms in the myeloid lineage and their role during aging and macrophage polarization
Authors: Aristorena Mikel , Blanco Francisco J. , de Las Casas-Engel Mateo , Ojeda-Fernandez Luisa , Gallardo-Vara Eunate , Corbi Angel , Botella Luisa M. , Bernabeu Carmelo
Published: April 2014

Endoglin plays a crucial role in physiopathological processes such as Hereditary Hemorrhagic Telangiectasia (HHT), preeclampsia or cancer. Endoglin expression is upregulated during the monocyte-to-macrophage transition, but little is known about its regulation and function in these immune cells. Two different alternatively spliced isoforms of endoglin have been reported, L-endoglin and S-endoglin. While L-endoglin is the predominant variant, an increased expression of the S-endoglin isoform during senescence of the myeloid lineage, in human and murine models, was observed. We performed a stable isotope labelling of amino acids in cell culture (SILAC) analysis of both L-endoglin and S-endoglin transfectants in the human promonocytic cell line U937. Analysis of differentially expressed protein clusters allowed the identification of cellular activities affected during aging. S-endoglin expression led to decreased cellular proliferation and survival response to GM-CSF-induced apoptosis, as well as increased oxidative stress. Gene expression and functional studies suggest a non-redundant role for each endoglin isoform in monocyte biology. In addition, we find that S-endoglin impairs the monocytic differentiation into the pro-inflammatory M1 phenotype and contributes to the compromised status of macrophage functions during aging.