bluuebunny/crossref_metadata_2025 huggingface dataset:
Achieving Sufficient Accrual to Address the Primary Endpoint in Phase III Clinical Trials from U.S. Cooperative Oncology Groups
Authors: Schroen Anneke T. , Petroni Gina R. , Wang Hongkun , Thielen Monika J. , Gray Robert , Benedetti Jacqueline , Wang Xiaofei F. , Sargent Daniel J. , Wickerham Donald L. , Cronin Walter , Djulbegovic Benjamin , Slingluff Craig L.
Published: October 2011

Purpose: Assessing impact of poor accrual on premature trial closure requires a relevant metric. We propose defining accrual sufficiency on apparent ability to address primary endpoints (PE) rather than attaining accrual targets.

Experimental Design: All phase III trials open January 1, 1993, to December 31, 2002, by five U.S. oncology Clinical Trials Cooperative Groups (CTCG) were evaluated for accrual sufficiency and scientific results. Sufficient accrual included meeting accrual target, CTCGs documentation attesting adequate accrual, or conclusive results at interim analysis; insufficient accrual included poor accrual as cited closure reason or other reasons rendering a trial unable to address its primary endpoints. Closure rates based on our accrual sufficiency definition are compared with rates of meeting accrual targets and addressing the primary endpoints. A percentage of target accrual above which trials commonly answer the intended scientific question was identified to serve as an alternative to meeting full target accrual in designating accrual success.

Results: Of 238 eligible trials, 158 (66%) closed with sufficient accrual. Among 80 trials with insufficient accrual, 70 (29%) closed specifically because of poor accrual. Inadequate accrual rates are overemphasized when defining accrual success solely by meeting accrual targets. Nearly 75% of trials conclusively addressed the primary endpoints with positive results in 39% of trials. Exceeding 80% of target accrual serves as a reliable proxy for answering the intended scientific question.

Conclusions: Approximately one third of phase III trials closed with insufficient accrual to address the primary endpoints, primarily due to poor accrual. Defining accrual sufficiency broader than meeting accrual targets represents a fairer account of trial closures. Clin Cancer Res; 18(1); 256–62. ©2011 AACR.
Endothelial-Derived Hyperpolarization Factor (EDHF) Contributes to PlGF-Induced Dilation of Mesenteric Resistance Arteries from Pregnant Rats
Authors: Mandalà Maurizio , Gokina Natalia , Barron Carolyn , Osol George
Published: October 2011

The aim of this study was to investigate the cellular mechanism involved in the potent vasodilatory action of PlGF on mesenteric resistance arteries from pregnant rats. PlGF (3 nM) induced a vasodilation of 64 ± 3.8% that was completely abolished by endothelial denudation. Significant dilation (28 ± 4.0%) remained, however, in the presence of nitric oxide synthase and cyclooxygenase inhibition, and was associated with significant reductions in vascular smooth muscle cell calcium. Absence of dilation in potassium-depolarizing solution (30 mM) confirmed its dependence on endothelial-derived hyperpolarization factor. Subsequent studies established that vasodilation was abolished by pharmacologic inhibition of SKCa (apamin) and BKCa (iberiotoxin) but not IKCa (tram-34) potassium channels. In summary, PlGF acts through the release of a combination of endothelium-derived relaxation factors. Based on the results of potassium channel blockade, we suggest that it induces endothelial hyperpolarization via SKCa channel activation; this, in turn, leads to the release of a diffusible mediator that activates vascular smooth muscle BKCa channels, hyperpolarization and vasodilation. This is the first study to identify the mechanism for PlGF/VEGFR-1 resistance artery dilation in the pregnant state, whose attenuation likely contributes to the systemic hypertension characteristic of pre- eclampsia.
Morphological and Functional Alterations in the Aorta of the Chronically Hypoxic Fetal Rat
Authors: Herrera Emilio A. , Camm Emily J. , Cross Christine M. , Mullender Joanne L. , Wooding F.B. Peter , Giussani Dino A.
Published: October 2011

In human pregnancy, reduced placental perfusion has been associated with fetal aortic thickening. However, the relative contributions of fetal undernutrition versus fetal underoxygenation to triggering alterations in fetal cardiovascular development remain uncertain. Here, we isolate the effects of chronic fetal hypoxia on fetal cardiovascular development in a specific rodent model of chronic fetal hypoxia independent of changes in nutrition during pregnancy. Pregnant rats were housed under normoxic (21% O2) or hypoxic (13% O2) conditions from day 6 to day 20 of gestation. At day 20, pups and placentas were weighed. Fetal thoraces were fixed for quantitative histological analysis of the aorta. In a separate group, fetal aortic reactivity was assessed via in vitro wire myography. The experiments controlled for sex and within-litter variation. Placental weight was increased and fetal weight maintained in hypoxic pregnancy. Hypoxic pregnancy led to a 176% increment in wall thickness and a 170% increment in the wall-to-lumen area ratio of the fetal aorta. Fetal aortic vascular reactivity was markedly impaired, showing reduced constrictor and relaxant responsiveness in hypoxic pregnancy. Chronic developmental hypoxia independent of changes in nutrition has profound effects on the morphology and function of the fetal aorta in a mammalian species.
Coronary Artery Angiographic Changes in Veterans Poisoned by Mustard Gas
Authors: Shabestari Mahmoud M. , Jabbari Farahzad , Gohari Behnaz , Moazen Nasrin , Azizi Hoda , Moghiman Toktam , Ibrahimzadeh Saeed , Amirabadi Amir
Published: October 2011

Objectives: We aimed to identify coronary artery involvement in mustard gas-poisoned patients. Methods: We conducted a case-control study on 40 mustard gas-poisoned patients who underwent coronary artery angiography due to cardiac pain. The study was performed during a 3-year interval on patients who were referred to three main hospitals of Mashhad, Iran. The nonexposed control group consisted of 40 normal individuals who had undergone angiography for the same reasons. The primary outcome measurement was coronary artery involvement and its location. Data were collected through studying the angiography films. Results: Among the 40 poisoned patients studied, 15 (37.5%) had coronary artery ectasia, mainly in the left anterior descending artery, but 25 (62.5%) did not. The same values were 2 (5%) and 38 (95%) in the nonexposed group, respectively, which was significantly different compared to the exposed group (p = 0.001). The odds ratio was 11.40. Conclusions: The prevalence of coronary artery ectasia in mustard gas-poisoned patients was 7.5 times more than in nonexposed controls. Considering the proposed odds ratio, the occurrence of coronary artery ectasia is around 11.4 times greater in mustard gas-poisoned veterans. This is the first study to suggest a strong correlation between mustard gas poisoning and coronary artery ectasia.
Relationship between Atrial Fibrillation and Gastroesophageal Reflux Disease: A Multicenter Questionnaire Survey
Authors: Shimazu Hideki , Nakaji Gen , Fukata Mitsuhiro , Odashiro Keita , Maruyama Toru , Akashi Koichi ,   on behalf of the Fukuoka F-Scale Trial Group
Published: October 2011

Objectives: The relationship between atrial fibrillation (AF) and gastroesophageal reflux disease (GERD) remains controversial, and investigations into this relationship have been based on small series. This multicenter survey evaluated the relationship between these diseases. Methods: The study enrolled 188 consecutive subjects (110 males and 78 females, mean age 60.4 ± 0.9 years) treated as outpatients. Patients were classified by the frequency scale for symptoms of GERD (F-scale) after obtaining informed consent for screening for GERD. Scores on this questionnaire were correlated to baseline characteristics obtained from medical records. The cutoff value for a diagnosis of GERD was set at 8.0 points. Results: Total scores on the F-scale were significantly greater in female subjects (p = 0.004) and in patients with AF (p = 0.019) compared to the other subjects. Univariate and multivariate analysis of the prevalence of GERD demonstrated that GERD was not related to gender, hypertension, dyslipidemia or coronary artery disease and that AF alone showed a significant (p < 0.001) correlation with GERD. Conclusions: This multicenter questionnaire survey demonstrated that among traditional cardiovascular risk factors, AF was an independent risk factor for GERD. A large cohort study to assess the potential relationship between GERD and AF is warranted.
Cellular immunity, low-density lipoprotein and atherosclerosis: Break of tolerance in the artery wall
Authors: Ketelhuth Daniel , Hansson Göran
Published: October 2011

Atherosclerosis is a chronic inflammatory disease. Atherosclerotic plaques contain abundant immune cells that can dictate and effect inflammatory responses. Among them, T cells are present during all stages of the disease suggesting that they are essential in the initiation as well as the progression of plaque. Experimental as well as clinical research has demonstrated different T cell subsets, i.e. CD4+ Th1, Th2, Th17, and Treg as well as CD8+ and NKT cells in the plaque. Moreover, candidate antigens inducing T cell responses have been identified. Knowledge about the pathological role of these cells in atherogenesis may lead to development of new therapies. This review provides an overview of the research field of cellular immunity in atherosclerosis. It emphasises the events and findings involving antigen specific T cells, in particular low-density lipoprotein-specific T cells.
Diabetes does not influence activation of coagulation, fibrinolysis or anticoagulant pathways in Gram-negative sepsis (melioidosis)
Authors: Meijers Joost , Maude Rapeephan , Limmathurotsakul Direk , Day Nicholas , Peacock Sharon , Poll Tom , Wiersinga Willem , Koh Gavin
Published: October 2011

Diabetes is associated with a disturbance of the haemostatic balance and is an important risk factor for sepsis, but the influence of diabetes on the pathogenesis of sepsis remains unclear. Melioidosis (Burkholderia pseudomallei infection) is a common cause of community-acquired sepsis in Southeast Asia and northern Australia. We sought to investigate the impact of pre-existing diabetes on the coagulation and fibrinolytic systems during sepsis caused by B. pseudomallei. We recruited a cohort of 44 patients (34 with diabetes and 10 without diabetes) with culture-proven melioidosis. Diabetes was defined as a pre-admission diagnosis of diabetes or an HbA1c>7.8% at enrolment. Thirty healthy blood donors and 52 otherwise healthy diabetes patients served as controls. Citrated plasma was collected from all subjects; additionally in melioidosis patients follow-up specimens were collected seven and ≥28 days after enrolment where possible. Relative to uninfected healthy controls, diabetes per se (i.e. in the absence of infection) was Characterised by a procoagulant effect. Melioidosis was associated with activation of coagulation (thrombin-antithrombin complexes (TAT), prothrombin fragment F1+2 and fibrinogen concentrations were elevated; PT and PTT prolonged), suppression of anti-coagulation (antithrombin, protein C, total and free protein S levels were depressed) and abnormalities of fibrinolysis (D-dimer and plasmin-antiplasmin complex [PAP] were elevated). Remarkably, none of these haemostatic alterations were influenced by pre-existing diabetes. In conclusion, although diabetes is associated with multiple abnormalities of coagulation, anticoagulation and fibrinolysis, these changes are not detectable when superimposed on the background of larger abnormalities attributable to B. pseudomallei sepsis.
Dave Eggers’s A Heartbreaking Work of Staggering Genius
Authors: Miller Elise
Published: October 2011

Dave Eggers’s memoir is an important addition to the tradition of autobiography in America, and offers significant contributions to our understanding of creativity, sublimation, and the psychology of the memoir-writing process. A Heartbreaking Work of Staggering Genius is really two books—an autobiographical narrative about unbearable suffering, and a book of psychoanalytic commentary on the challenges of writing a memoir about catastrophic loss and trauma. The main narrative suggests the psychological resilience it takes to contain unbearable suffering. The metanarrative renders transparent the mind of someone who is both remembering his losses and constantly reflecting upon the process of writing about them. Eggers’s identification with authorship, rather than bereavement or traumatization, may have played an important role in containing his affect and his sense of self when the heartbreaking events were originally unfolding. But a price is paid when a son uses his art to construct a new identity as an author—unconscious conflicts, primitive affect, anxieties about failing, as well as guilt about succeeding—consequences often missed by readers. Heartbreaking is a palimpsest, a story about story-telling superimposed on tales of death and survival, but its messages will be missed unless all its parts are preserved when being read or studied.
The People Shall Be Judge
Authors: Vatter Miguel
Published: October 2011

This essay offers an interpretation of Kant’s republicanism in light of the problem of political judgment. Kant is sometimes thought to base his conception of law on an idea of sovereignty drawn from Hobbes and Rousseau, which would leave little room for popular contestation of the state. In this essay, I reconstruct Kant’s account of the rule of law by bringing out the importance of his theory of judgment. I argue that for Kant the civil condition is ultimately characterized by a contest between the judgment of the sovereign and the judgment of the people, which corresponds to the determinative and reflective employments of political judgment, respectively. On this view, popular sovereignty is ultimately located in the people’s power to judge politically and contest publicly the state.
Indigenous Resistance and the Law
Authors: Vanegas Farid Samir Benavides
Published: October 2011

The indigenous peoples of Colombia have used various forms of resistance to attempt to change their identities and appropriate their lands. Over time the emphasis has shifted from law and legal titles to marches and land occupations to armed resistance and back again to the law. The legal liberalism that emerged with the 1991 Constitution in Colombia led to the demobilization of the indigenous movement of the time as marches and land occupations were abandoned in favor of lawsuits that identified violations of rights. Success in the courts did not result in any change in the government’s policies or its model of development. As the focus shifted from the local to the national level, indigenous peoples’ problems on the ground remained unresolved. In recent years, however, local organizations have rediscovered old forms of resistance and use the law as just one tool among many for protecting their rights.

Los indígenas colombianos han empleado diversas estrategias de resistencia en sus intentos por cambiar su identidad y conservar sus tierras. Lo que en un principio se manifestó como apelaciones a la ley y títulos legales dio, posteriormente, lugar a marchas, ocupación de tierras y resistencia armada, para eventualmente volver a la ley. El liberalismo legal producto de la Constitución de 1991 llevó a la desmovilización del movimiento indígena y las marchas y ocupaciones fueron sustituidas por demandas legales en torno a violación de derechos. Los éxitos obtenidos en la corte, sin embargo, no alteraron la política gubernamental o el modelo de desarrollo. Conforme la atención pasó de los niveles locales al entorno nacional, los problemas indígenas continuaron sin resolución alguna. Recientemente, algunas organizaciones locales han redescubierto antiguas formas de resistencia y utilizan la ley como una herramienta más para proteger sus derechos.
Beyond Testing: Social and Psychological Considerations in Recruiting and Retaining Gifted Black Students
Authors: Ford Donna Y. , Whiting Gilman W.
Published: October 2011

For more than a half century, concerns have existed about the persistent underrepresentation of African American students in gifted education and Advanced Placement classes. Various recommendations to reverse underrepresentation have been proposed, with the majority focusing on testing and assessment instruments. Nonetheless, progress has been inadequate as underrepresentation persists at high levels nationally, especially among Black males. Clearly, we must continue to find more effective tests and instruments, but we cannot stop there. In this article, we propose that, in the process of focusing on more effective ways to recruit and retain African American students, greater attention must be given to social and psychological factors, namely peer pressures and racial identity. Equally important, we must consider gender—the differential experiences of Black males and females. The discussion of these issues is followed by recommendations for change for educators.
Mathematical Problem Preferences of Meaning-Oriented and Number-Oriented Problem Solvers
Authors: Garofalo Joe
Published: October 2011

This article reports on the problem preferences of meaning-oriented and number-oriented mathematical problem solvers. In general, very successful meaning-oriented students expressed preferences for solving multi-step and non-routine problems, while, not surprisingly, less successful number-oriented students expressed preferences for simple routine problems. However, when in graded situations, even the very successful students preferred simple problems. Reasons for these preferences are discussed, along with some of their implications for teaching mathematics to meaning-oriented students.
The Effect of Synectics Training on Gifted and Nongifted Kindergarten Students
Authors: Meador Karen S.
Published: October 2011

The purpose of this study was to determine the effect of synectics training on the development of creativity, self-concept, and verbal skills of kindergarten students who were gifted and nongifted. The Figural Form of the Torrance Tests of Creativity, the Martinek Zaichkowsky Self-Concept Scale, and the Peabody Picture Vocabulary Test were administered as pre- and posttests to 107 subjects. A series of two-way analyses of covariance was used to analyze the effect of synectics training. Significant improvement in creativity scores was found for the experimental groups as compared to the control groups, but not for gifted vs. nongifted children. A post hoc analysis in the level of response for the gifted and nongifted experimental groups showed qualitative differences worthy of future study.
Possible role of the JAK/STAT pathways in the regulation of T cell-interferon related genes in systemic lupus erythematosus
Authors: Kawasaki M , Fujishiro M , Yamaguchi A , Nozawa K , Kaneko H , Takasaki Y , Takamori K , Ogawa H , Sekigawa I
Published: October 2011

Changes in gene expression in CD3+ T cells associated with disease progression in systemic lupus erythematosus (SLE) patients were determined. The genes related to SLE disease-related activities were identified and their gene regulatory networks were investigated. Analyses of gene expression were performed by both DNA microarray and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The expression of certain genes including interferon (IFN) regulatory factor (IRF)-related genes, such as IFN-regulated, -related, and -signature genes was increased in the active phase of SLE. Pathway network analyses suggested that these IRF-related genes are regulated through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. JAK/STAT pathway-mediated regulation of IRF-related genes may have an important role in the disease activity of SLE. Inhibitors of JAK/STAT cascade may be useful as therapeutic agents.
1H NMR-based metabolomic study of metabolic profiling for systemic lupus erythematosus
Authors: Ouyang X , Dai Y , Wen JL , Wang LX
Published: October 2011

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterized by multi-system involvement, diverse clinical presentation, and alterations in circulating metabolites. In this study, a 1H NMR spectroscopy-based metabolomics approach was applied to establish a human SLE serum metabolic profile. Serum samples were obtained from patients with SLE ( n = 64), patients with rheumatoid arthritis (RA) ( n = 30) and healthy controls ( n = 35). The NOESYPR1D spectrum combined with multi-variate pattern recognition analysis was used to cluster the groups and establish a disease-specific metabolites phenotype. Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) models were capable of distinguishing SLE or RA patients from healthy subjects. The OPLS-DA model was able to predict diagnosis of SLE with a sensitivity rate of 60.9% and a specificity rate of 97.1%. For diagnosing RA, the model has much higher sensitivity (96.7%) and specificity (91.4%). The SLE serum samples were characterized by reduced concentrations of valine, tyrosine, phenylalanine, lysine, isoleucine, histidine, glutamine, alanine, citrate, creatinine, creatine, pyruvate, high-density lipoprotein, cholesterol, glycerol, formate and increased concentrations of N-acetyl glycoprotein, very low-density lipoprotein and low-density lipoprotein in comparison with the control population. Theresults not only indicated that serum NMR-based metabolomic methods had sufficient sensitivity and specificity to distinguish SLE and RA from healthy controls, but also have the potential to be developed into a clinically useful diagnostic tool, and could also contribute to a further understanding of disease mechanisms.
Aggravated capillary non-perfusion after intravitreal bevacizumab for macular edema secondary to systemic lupus erythematosus and anti-phospholipid syndrome
Authors: Jeon S , Lee WK
Published: October 2011

A 22-year-old female with history of systemic lupus erythematosus (SLE) was referred for evaluation of decreased visual acuity in her right eye. Her best-corrected visual acuity (BCVA) at the time of presentation was 20/160. Widespread cotton wool spots and macular edema were seen on biomicroscopy. Fluorescein angiography (FA) revealed retinal arterial and venous obstruction with capillary nonperfusion at the superotemporal retina. Antiphospholipid syndrome (APS) was diagnosed based on positive lupus anti-coagulant and ocular manifestations. Scattered laser photocoagulation was applied at the nonperfusion area but the visual acuity continued to deteriorate due to macular edema. Intravitreal bevacizumab (IVB) was administered for macular edema. One day after IVB, the BCVA decreased to count fingers. FA revealed extended non-perfusion from the superotemporal area to the posterior pole. Use of intravitreal bevacizumab for macular edema secondary to SLE or APS should be considered carefully and patients monitored closely for vascular complications.
Orthodox Jewish perspectives on withholding and withdrawing life-sustaining treatment
Authors: Baeke Goedele , Wils Jean-Pierre , Broeckaert Bert
Published: October 2011

The Jewish religious tradition summons its adherents to save life. For religious Jews preservation of life is the ultimate religious commandment. At the same time Jewish law recognizes that the agony of a moribund person may not be stretched. When the time to die has come this has to be respected. The process of dying should not needlessly be prolonged. We discuss the position of two prominent Orthodox Jewish authorities – the late Rabbi Moshe Feinstein and Rabbi J David Bleich – towards the role of life-sustaining treatment in end-of-life care. From the review, the characteristic halachic and heterogeneous character of Jewish ethical reasoning appears. The specificity of Jewish dealing with ethical dilemmas in health care indicates the importance for contemporary healthcare professionals of providing care which is sensitive to a patient’s culture and worldview.
Collective narcissism and anti-Semitism in Poland
Authors: Golec de Zavala Agnieszka , Cichocka Aleksandra
Published: October 2011

Two studies examined the relationship between collective narcissism—an emotional investment in an unrealistic belief about the greatness of an in-group (Golec de Zavala, Cichocka, Eidelson, & Jayawickreme, 2009) — and anti-Semitism in Poland. The results indicate that this relationship is simultaneously mediated by (a) a belief that the in-group is constantly threatened by hostile intentions of other groups (Polish siege beliefs; Bar-Tal & Antebi, 1992a , 1992b ) and (b) a belief that the Jews are a particularly threatening out-group because they secretly aim to dominate the world (the conspiracy stereotype of Jews; Bergmann, 2008 ; Kofta & Sędek, 2005 ). These results confirm that collective narcissism predicts prejudice against social groups perceived as threatening. Collective narcissists’ sensitivity to intergroup threat is composed of beliefs about vulnerability of the in-group and hostility of the out-group.
Aspiration and Swallowing Dysfunction in Pediatric Patients
Authors: Miller Claire Kane
Published: October 2011

Early identification and management of aspiration associated with oral intake will help contribute to the best possible outcome for infants and children who have airway protection issues with swallowing. Though the incidence and prevalence of aspiration specifically related to swallowing dysfunction across medical conditions in the pediatric population is unknown, there is accumulating evidence of swallowing-related aspiration in infants and children with diagnoses that include structural abnormalities of the upper airway, central nervous system abnormalities, and progressive neurological disease. Chronic aspiration is associated with compromised respiratory health, progressive lung disease, bronchiectasis, and respiratory failure; thus, early detection and appropriate management is crucial. Determining the etiology and effect of aspiration is complex, and multiple evaluations are often required. This article will focus on instrumental studies of swallowing physiology used in the diagnosis and management of swallowing dysfunction and aspiration. Therapeutic strategies to improve airway protection during swallowing will also be described.
A retrospective cohort study of stroke onset: implications for characterizing short term effects from ambient air pollution
Authors: Johnson Julie YM , Villeneuve Paul J , Pasichnyk Dion , Rowe Brian H
Published: October 2011

Background

Case-crossover studies used to investigate associations between an environmental exposure and an acute health response, such as stroke, will often use the day an individual presents to an emergency department (ED) or is admitted to hospital to infer when the stroke occurred. Similarly, they will use patient's place of residence to assign exposure. The validity of using these two data elements, typically extracted from administrative databases or patient charts, to define the time of stroke onset and to assign exposure are critical in this field of research as air pollutant concentrations are temporally and spatially variable. Our a priori hypotheses were that date of presentation differs from the date of stroke onset for a substantial number of patients, and that assigning exposure to ambient pollution using place of residence introduces an important source of exposure measurement error. The objective of this study was to improve our understanding on how these sources of errors influence risk estimates derived using a case-crossover study design.

Methods

We sought to collect survey data from stroke patients presenting to hospital EDs in Edmonton, Canada on the date, time, location and nature of activities at onset of stroke symptoms. The daily mean ambient concentrations of NO2 and PM2.5 on the self-reported day of stroke onset was estimated from continuous fixed-site monitoring stations.

Results

Of the 336 participating patients, 241 were able to recall when their stroke started and 72.6% (95% confidence interval [CI]: 66.9 - 78.3%) experienced stroke onset the same day they presented to the ED. For subjects whose day of stroke onset differed from the day of presentation to the ED, this difference ranged from 1 to 12 days (mean = 1.8; median = 1). In these subjects, there were no systematic differences in assigned pollution levels for either NO2 or PM2.5 when day of presentation rather than day of stroke onset was used. At the time of stroke onset, 89.9% (95% CI: 86.6 - 93.1%) reported that they were inside, while 84.5% (95% CI: 80.6 - 88.4%) reported that for most of the day they were within a 15 minute drive from home. We estimated that due to the mis-specification of the day of stroke onset, the risk of hospitalization for stroke would be understated by 15% and 20%, for NO2 and PM2.5, respectively.

Conclusions

Our data suggest that day of presentation and residential location data obtained from administrative records reasonably captures the time and location of stroke onset for most patients. Under these conditions, any associated errors are unlikely to be an important source of bias when estimating air pollution risks in this population.
Blow-up for an evolution p-laplace system with nonlocal sources and inner absorptions
Authors: Zhang Yan , Liu Dengming , Mu Chunlai , Zheng Pan
Published: October 2011

This paper investigates the blow-up properties of positive solutions to the following system of evolution p-Laplace equations with nonlocal sources and inner absorptions

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2010 Mathematics Subject Classification: 35B35; 35K60; 35K65; 35K57.
The use of complete-case and multiple imputation-based analyses in molecular epidemiology studies that assess interaction effects
Authors: Desai Manisha , Esserman Denise A , Gammon Marilie D , Terry Mary B
Published: October 2011

Background

In molecular epidemiology studies biospecimen data are collected, often with the purpose of evaluating the synergistic role between a biomarker and another feature on an outcome. Typically, biomarker data are collected on only a proportion of subjects eligible for study, leading to a missing data problem. Missing data methods, however, are not customarily incorporated into analyses. Instead, complete-case (CC) analyses are performed, which can result in biased and inefficient estimates.

Methods

Through simulations, we characterized the performance of CC methods when interaction effects are estimated. We also investigated whether standard multiple imputation (MI) could improve estimation over CC methods when the data are not missing at random (NMAR) and auxiliary information may or may not exist.

Results

CC analyses were shown to result in considerable bias and efficiency loss. While MI reduced bias and increased efficiency over CC methods under specific conditions, it too resulted in biased estimates depending on the strength of the auxiliary data available and the nature of the missingness. In particular, CC performed better than MI when extreme values of the covariate were more likely to be missing, while MI outperformed CC when missingness of the covariate related to both the covariate and outcome. MI always improved performance when strong auxiliary data were available. In a real study, MI estimates of interaction effects were attenuated relative to those from a CC approach.

Conclusions

Our findings suggest the importance of incorporating missing data methods into the analysis. If the data are MAR, standard MI is a reasonable method. Auxiliary variables may make this assumption more reasonable even if the data are NMAR. Under NMAR we emphasize caution when using standard MI and recommend it over CC only when strong auxiliary data are available. MI, with the missing data mechanism specified, is an alternative when the data are NMAR. In all cases, it is recommended to take advantage of MI's ability to account for the uncertainty of these assumptions.
Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease
Authors: Jiang Hong , Hampel Harald , Prvulovic David , Wallin Anders , Blennow Kaj , Li Rena , Shen Yong
Published: October 2011

We recently reported that expression levels of tumor necrosis factor (TNF) receptors, TNFR1 and TNFR2, are significantly changed in the brains and cerebrospinal fluid (CSF) with Alzheimer's disease (AD). Moreover, we also found that, in an Alzheimer's mouse model, genetic deletion of TNF receptor (TNFR1) reduces amyloid plaques and amyloid beta peptides (Aβ) production through β-secretase (BACE1) regulation. TNF-α converting enzyme (TACE/ADAM-17) does not only cleave pro- TNF-α but also TNF receptors, however, whether the TACE activity was changed in the CSF was not clear. In this study, we examined TACE in the CSF in 32 AD patients and 27 age-matched healthy controls (HCs). Interestingly, we found that TACE activity was significantly elevated in the CSF from AD patients compared with HCs. Furthermore, we also assayed the CSF levels of TACE cleaved soluble forms of TNFR1 and TNFR2 in the same patients. We found that AD patients had higher levels of both TACE cleaved soluble TNFR1 (sTNFR1) and TNFR2 (sTNFR2) in the CSF compared to age- and gender-matched healthy controls. Levels of sTNFR1 correlated strongly with the levels of sTNFR2 (rs = 0.567-0.663, p < 0.01). The levels of both sTNFR1 and sTNFR2 significantly correlated with the TACE activity (rs = 0.491-0.557, p < 0.05). To examine if changes in TACE activity and in levels of cleaved soluble TNFRs are an early event in the course of AD, we measured these molecules in the CSF from 47 subjects with mild cognitive impairment (MCI), which is considered as a preclinical stage of AD. Unexpectedly, we found significantly higher levels of TACE activity and soluble TNFRs in the MCI group than that in AD patients. These results suggest that TACE activity and soluble TNF receptors may be potential diagnostic candidate biomarkers in AD and MCI.
A clinically relevant gene signature in triple negative and basal-like breast cancer
Authors: Rody Achim , Karn Thomas , Liedtke Cornelia , Pusztai Lajos , Ruckhaeberle Eugen , Hanker Lars , Gaetje Regine , Solbach Christine , Ahr Andre , Metzler Dirk , Schmidt Marcus , Müller Volkmar , Holtrich Uwe , Kaufmann Manfred
Published: October 2011

Introduction

Current prognostic gene expression profiles for breast cancer mainly reflect proliferation status and are most useful in ER-positive cancers. Triple negative breast cancers (TNBC) are clinically heterogeneous and prognostic markers and biology-based therapies are needed to better treat this disease.

Methods

We assembled Affymetrix gene expression data for 579 TNBC and performed unsupervised analysis to define metagenes that distinguish molecular subsets within TNBC. We used n = 394 cases for discovery and n = 185 cases for validation. Sixteen metagenes emerged that identified basal-like, apocrine and claudin-low molecular subtypes, or reflected various non-neoplastic cell populations, including immune cells, blood, adipocytes, stroma, angiogenesis and inflammation within the cancer. The expressions of these metagenes were correlated with survival and multivariate analysis was performed, including routine clinical and pathological variables.

Results

Seventy-three percent of TNBC displayed basal-like molecular subtype that correlated with high histological grade and younger age. Survival of basal-like TNBC was not different from non basal-like TNBC. High expression of immune cell metagenes was associated with good and high expression of inflammation and angiogenesis-related metagenes were associated with poor prognosis. A ratio of high B-cell and low IL-8 metagenes identified 32% of TNBC with good prognosis (hazard ratio (HR) 0.37, 95% CI 0.22 to 0.61; P < 0.001) and was the only significant predictor in multivariate analysis including routine clinicopathological variables.

Conclusions

We describe a ratio of high B-cell presence and low IL-8 activity as a powerful new prognostic marker for TNBC. Inhibition of the IL-8 pathway also represents an attractive novel therapeutic target for this disease.
Case Article—Teaching Soft Systems Methodology and a Blueprint for a Module
Authors: Hindle Giles A.
Published: October 2011

This paper reflects upon the teaching of soft systems methodology (SSM) to undergraduate, postgraduate, and executive students. The paper presents SSM as an all-purpose approach to tackling complex situations, which can be conceived as an experiential learning cycle. SSM adopts a participative approach to problem solving and uses systems modeling to structure discussion between stakeholders. After introducing the basic nature of SSM, the paper discusses issues with teaching it. These are seen to stem from the flexible nature of SSM and the unusual modeling language. An example case study and module blueprint are then presented that have proved successful with preexperience and postexperience students. The teaching approach is based upon the principles of experiential learning and the paper shows how a realistic consulting project helps students to experience the use of SSM and grasp the nature of the systems modeling. The paper argues that student groups need to be facilitated though role-play to achieve a productive experience and acceptable analytic outcomes.
Abstracting and Engaging: Two Modes of Systems Thinking Education
Authors: Córdoba-Pachón José-Rodrigo
Published: October 2011

This paper presents two modes of systems thinking education to help make sense of previous and future experiences in this field as well as in soft operational research in general. Using Abbott's ideas on professional knowledge I present these modes as based on either (1) abstracting or (2) engaging. The former emphasises the value of systems thinking in helping people understand abstractions to deal with complex situations. The latter focuses on using abstractions to facilitate students' engagement with complex situations in areas outside operational research including sustainability and project management. I present each mode based on my experience in a higher education setting in the UK, and I highlight key elements and possibilities for these modes that could inform future developments in systems thinking and operational research education.
A Lagrangian Heuristic for Robustness, with an Application to Train Timetabling
Authors: Cacchiani Valentina , Caprara Alberto , Fischetti Matteo
Published: October 2011

Finding robust yet efficient solutions to optimization problems is a major practical issue that received large attention in recent years. Starting with stochastic programming, many of the approaches to robustness lead to a significant change in the problem formulation with respect to the nonrobust (nominal) case. Besides requiring a much larger computational effort, this often results into major changes of the associated software.

Lagrangian heuristics form a wide family of methods that work well in finding efficient (i.e., low-cost) solutions for many problems. These methods approximately solve a relaxation of the problem at hand through an iterative Lagrangian optimization scheme and apply several times a basic heuristic driven by the Lagrangian dual information (typically, the current Lagrangian costs) so as to update the current best feasible solution. In this context, the underlying Lagrangian optimization iterative method has the main purpose of producing “increasingly reliable” Lagrangian costs, while diversifying the search in the last iterations, when the Lagrangian bound is very close to convergence.

The purpose of this paper is to propose, for the first time, to the best of our knowledge, a very simple modification of the Lagrangian optimization scheme capable of dealing with robustness. This modification is based on two simple features: (a) We modify the problem formulation by introducing artificial parameters intended to “control” the solution robustness and (b) during Lagrangian optimization, we dynamically change the weight of the control parameters to produce subproblems where robustness becomes more and more important. In this way, during the process we can easily collect a set of, roughly speaking, “Pareto optimal” heuristic solutions that have a different trade-off between robustness and efficiency and leave the final user the choice of the ones to analyze in more details—e.g., through a time-consuming validation tool.

As a proof-of-concept, our approach is applied to the well-known aperiodic train timetabling problem on a corridor and is computationally analyzed on real-world test cases from the Italian Railways, showing that it produces within much shorter computing times solutions whose quality is comparable with those produced by existing approaches to robustness. This proves the effectiveness for the specific application, suggesting that a simple modification of existing Lagrangian heuristics is a very promising way to deal with robustness in many other cases.
Reaction of OH and NO at Low Temperatures in the Presence of Water: the Role of Clusters
Authors: Liessmann Matthias , Miller Yifat , Gerber Benny , Abel Bernd
Published: October 2011

There has been a lot of speculation about the role of water in gas phase reactions involving neutrals, radicals and ions. The reaction of NO and OH has attracted a lot of attention in the past due to its relevance for ozone chemistry in the atmosphere. In the present contribution we report low temperature measurements of the recombination of OH and NO at low temperatures in Laval nozzle expansions between 300 K and 60 K. We find an increase of the bimolecular rate constant in the presence of water of up to 40%. This effect has been attributed to water molecules acting either as an efficient collider releasing energy from the intermediate (in collisions) or – which is more likely for the present experimental conditions – as a cluster partner of the reaction intermediate HONO that also dissipates energy via cluster dissociation, which can in turn both stabilize the reaction intermediate, decrease back reaction to OH and NO, and enh ance finally the overall reaction to the products. The supersaturation of water vapor in the cold Laval nozzle expansion strongly favors the formation of clusters in the nozzle throat; their exact concentration is, however, difficult to estimate due to non-equilibrium conditions. The possible role of clusters in the recombination of OH and NO is investigated using ab initio molecular dynamics calculations. Beyond the reaction intermediate HONO and intramolecular proton transfer events also transient HOON was observed in the theoretical study.
Computer program for distance learning of pesticide application technology
Authors: Maia Bruno , Cunha Joao P.A.R.
Published: October 2011

Distance learning presents great potential for mitigating field problems on pesticide application technology. Thus, due to the lack of teaching material about pesticide spraying technology in the Portuguese language and the increasing availability of distance learning, this study developed and evaluated a computer program for distance learning about the theory of pesticide spraying technology using the tools of information technology. The modules comprising the course, named Pulverizar, were: (1) Basic concepts, (2) Factors that affect application, (3) Equipments, (4) Spraying nozzles, (5) Sprayer calibration, (6) Aerial application, (7) Chemigation, (8) Physical-chemical properties, (9) Formulations, (10) Adjuvants, (11) Water quality, and (12) Adequate use of pesticides. The program was made available to the public on July 1st, 2008, hosted at the web site www.pulverizar.iciag.ufu.br, and was simple, robust and practical on the complementation of traditional teaching for the education of professionals in Agricultural Sciences. Mastering pesticide spraying technology by people involved in agricultural production can be facilitated by the program Pulverizar, which was well accepted in its initial evaluation.
Pesquisa de aglutininas, antígeno de leptospiras e apoptose em rim de suínos naturalmente infectados por Leptospira spp.
Authors: Gonçalves Larissa M.F. , Mineiro Ana Lys B.B. , Carvalho Sônia M. de , Campos Ângela P. , Evangelista Luanna S. de Melo , Pinho Flaviane A. , Moreira Élvio C. , Costa Francisco A.L.
Published: October 2011

Soro e rim de 75 suínos mestiços sem raça definida, criados em sistema extensivo e abatidos em Timon (MA) e Teresina (Piauí), Brasil, duas cidades separadas pelo Rio Parnaíba e 75 suínos mestiços de um sistema de criação em confinamento, filhos de Landrace, Large White e/ou Duroc foram utilizados neste estudo. Das 150 amostras analisadas pela prova de Soroaglutinação Microscópica (SAM), sete foram reagentes e o sorovar Icterohaemorrhagiae (42,86%) foi o mais frequente. Uma comparação entre os dois sistemas para examinar uma predisposição para infecção para Leptospira spp. mostrou que a suscetibilidade foi maior nos animais criados extensivamente do que naqueles criados em confinamento (teste χ2, p<0,05). A presença de infiltrado inflamatório foi significantemente maior nos animais soropositivos comparados aos soronegativos (p<0,05, Teste U de Mann-Whitney). A análise morfométrica mostrou Leptospira spp. e o antígeno de leptospira apenas nos animais soropositivos (p<0,05, teste de U de Mann-Whitney). Apoptose em células epiteliais tubulares foi significantemente mais evidente nos animais infectados comparados aos não infectados (p<0,05, Teste U de Mann-Whitney). Uma eventual associação de antígeno de Leptospira e células epiteliais em apoptose sugere um provável mecanismo de lesão renal na leptospirose suína.
Evaluation of PCR and multiplex PCR in relation to nested PCR for diagnosing Theileria equi
Authors: Leal Danielle C. , Madruga Cláudio R. , Matos Paulo F. de , Souza Bárbara M. P. da S. , Franke Carlos R.
Published: October 2011

Conventional PCR (PCRTeq) for diagnosing Theileria equi and multiplex PCR (M/PCRTeq-Bc) for diagnosing T. equi and Babesia caballi were comparatively evaluated with nested PCR (N/PCR-Teq) for diagnosing equine piroplasmosis. In DNA sensitivity determinations, in multiple dilutions of equine blood that had tested positive for T. equi, PCR-Teq and N/PCR-Teq detected hemoparasite DNA in the larger dilutions (1:128), but did not differ significantly from the M/PCRTeq-Bc (1:64). In analyses on equine serum tested by ELISA, there was high agreement between this serological test and PCR-Teq (k = 0.780) and moderate agreement with N/PCR-Teq (k = 0.562) and M/PCRTeq-Bc (k = 0.488). PCR-Teq found a higher frequency of T. equi both in extensively and intensively reared horses, but this was not significant in relation to N/PCR-Teq (P>0.05), and both PCRs indicated that there was an endemic situation regarding T. equi in the population of horses of this sample. PCR-Teq was only significantly different from M/PCR-Teq-Bc (P<0.05). PCR-Teq presented high sensitivity and specificity, comparable to N/PCR-Teq, but with the advantage of higher speed in obtaining results and lower costs and risks of laboratory contamination. This accredits PCR-Teq for epidemiological studies and for determinations on affected horses.