bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the effects of traveling speeds and post-weld heat treatment on mechanical properties of nano-Al2O3-fortified AA6061-T6 friction stir welds
Authors: Yousefpour Naghibi H , Omidvar H , Farahmand Nikoo M
Published: June 2016

In this study, 6 mm thick AA6061-T6 plates were friction stir welded (FSWed) at different traveling speeds while Al2O3 nano-particles were incorporated between adjoining plates. The solution heat treatment was applied on samples for one hour at 540 ℃ and subsequently aged for 18 h at 180 ℃ to investigate the effect of post-weld heat treatment on mechanical properties of specimens. All joints were investigated macro- and micro-structurally. The microstructural characterization of the FSWed samples was carried out using scanning electron microscopy (SEM) and light microscopy techniques. Distribution of Al2O3 nano-particles in the stir zone was studied by SEM. The specimen FSWed at 40 mm/min exhibited the most homogeneous particles distribution. Tensile properties including ultimate tensile strength, elongation, and fracture surfaces were studied. Microhardness of specimens was also investigated. Surprisingly, all specimens exhibited inferior hardness compared to the as-received AA6061-T6 alloy. This phenomenon was attributed to the dissolution of precipitates during FSW process.
Political participation in a Palestinian university: Nablus undergraduates’ political subjectivities through boredom, fear and consumption
Authors: Casati Noemi
Published: June 2016

While Palestine is often approached either as a site of ‘resistance’ or of recent neoliberal de-politicization, the case of young university students defeats dichotomous categorizations and points to the more complex and layered nature of political subjectivities. Drawing on unique ethnographic fieldwork as a student at Najah University in Nablus, this article addresses students’ political subjectivities against the backdrop of three macrochanges in Palestinian recent history: the professionalization of politics, the tightening of internal repression, and the neoliberal economic turn. Overall, the study argues that, while Najah undergraduates maintain a strong nationalist discourse, they have come to conceptualize ‘politics’ as negative, at once ineffective and dangerous. Caught up in a web of conflicting social expectations, the pessimism vis-à-vis the political field leads them to abandon traditional sites of participation and to adopt a cynical yet ultimately political approach to consumption in an attempt to ‘change air’ and ‘just live’.
An analysis of the psychosocial backgrounds of Youths (13–18) Who-Pose-Sexual-Risk to children
Authors: Williams Richard , Pritchard Colin
Published: June 2016

Social workers had expressed concern to their Local Safeguarding Children Board (LSCB) about male Youths (13–18)-Who-Pose-Sexual-Risk (YWPSR) to children, leading to this study of 36 social-history protocols, completed by the youths’ social workers, that identified the presence of research-based factors of YWPSR who then go on to become adult child sex offenders. To ensure total confidentiality, no actual case-record data were available to the authors, ensuring the LSCB, social workers and their clients remain totally anonymous. While a small sample poses methodological difficulties, the authors believe the data is worthy of consideration as a pilot study for a larger project that might highlight the potential areas for early intervention.

Findings

Key findings were: 29 (80%) of 36 YWPSR were <14 when first showing inappropriate sexual behaviour, whilst 25% were known to have been sexually abused themselves, mostly <11 years and 47% were either currently or had been, Looked-After-Children, with 42% having been Excluded-from-School of who 36% had learning difficulties. Their level of disturbance is shown by 11% having made a suicide attempt and they being formally charges for sex offences against children, which was significantly higher than that found in the adult general population. Finally 66% suffered from low self-esteem, were socially isolated and had poor peer relationships; reflected in the high level of problems at school.

Application

Such young people pose a challenge for all concerned and an evidence-based debate is required to explore how to prevent further unacceptable behaviour and thereby protect vulnerable children.
The initiation and development of combustion under cold idling conditions using a glow plug in diesel engines
Authors: Li Q , Shayler PJ , McGhee M , La Rocca A
Published: June 2016

Factors determining the success or failure of combustion initiation using a glow plug have been investigated through experimental work on a single cylinder, common rail diesel engine with a geometric compression ratio of 15.5, and a quiescent combustion bomb with optical access. A glow plug was required to avoid engine misfires when bulk gas temperature at the start of injection was less than 413 °C. The distance between the glow plug and the spray edge, the glow plug temperature, and the bulk gas temperature were important factors in meeting two requirements for successful ignition: a minimum local temperature of 413 °C and a minimum air/fuel vapour equivalence ratio of 0.15–0.35.
An empirical investigation of the dimensionality of the physical literacy environment in early childhood classrooms
Authors: Dynia Jaclyn M , Schachter Rachel E , Piasta Shayne B , Justice Laura M , O’Connell Ann A , Yeager Pelatti Christina
Published: June 2016

This study investigated the dimensionality of the physical literacy environment of early childhood education classrooms. Data on the classroom physical literacy environment were collected from 245 classrooms using the Classroom Literacy Observation Profile. A combination of confirmatory and exploratory factor analysis was used to identify five separate dimensions of the physical literacy environment; including (a) variety and use of books, (b) variety and use of writing centre materials, (c) variety and use of technology, (d) variety of environmental print and (e) variety and use of other literacy-related materials. Overall, these five dimensions demonstrated reasonable reliability and validity. Implications for investigating the physical literacy environment and future directions for research are discussed.
“City Inside the Oven”
Authors: Mukherjee Rahul
Published: June 2016

Since 2010, concerned citizens in India argued that cell antenna signals had heating effects on bodies, and media campaigns compared the experience of living in cities with cell towers as being inside the oven. I argue that mediation of cell towers in newspapers and lifestyle shows as potentially emitting cancer-causing radiation was key to shaping public perceptions about them. Through their disruptive nature, cell towers call into action a technoscience public consisting of a variety of stakeholders, including radio-frequency scientists, cellular operators, journalists, tower builders, activists, municipal corporations, and building owners. Technoscience publics and media publics intersect and shape each other, and this article presents “mediated technoscience public” as a theoretical framework for an ethnographic intervention in media studies. This framework involves the tracking and comparison of media coverage about technological infrastructure as well as the ways humans emotionally perceive and interact with those infrastructures.
“I May Need You, Peter, but You Sure as Hell Need Me Too”
Authors: Leonard Suzanne
Published: June 2016

Observing that contemporary marriages now represent transactional efforts that benefit wives as much as their spouses, this article considers The Good Wife’s Alicia Florrick alongside a list of real-life women, most notably Hillary Clinton, whose examples have helped to trouble and complicate the image of the betrayed wife. While marriage continues to register as a necessary complement to any political run, this fact is increasingly regarded with skepticism and a self-conscious admission that the performance of a happy union is often merely a tactical move, a reality that is well-evidenced in The Good Wife and the ABC drama Scandal. A meditation on Huma Abedin and Anthony Weiner, a real-life political couple who seem to be baldly borrowing from (or perhaps inspiring) these televised marriages, closes the piece and is used to suggest that political marriages may serve as professional boons.
Predictors of Discrepancy Between Care Recipients With Mild-to-Moderate Dementia and Their Caregivers on Perceptions of the Care Recipients’ Quality of Life
Authors: Moon Heehyul , Townsend Aloen L. , Dilworth-Anderson Peggye , Whitlatch Carol J.
Published: June 2016

Purpose:

The goal of this study was to explore predictors of discrepancy between reports of caregivers (CGs) and care recipients (CRs) with mild-to-moderate dementia about CRs’ quality of life (QOL).

Design and Methods:

This study was a secondary analysis of cross-sectional data drawn from a study of 200 care dyads of CRs with mild-to-moderate dementia and their primary family CGs. Paired t test, ordinary least squares multiple regression, and binary logistic regression were used for the analyses.

Results:

Caregivers rated CRs’ QOL significantly lower (worse) than CRs did. Ordinary least square regression results showed that greater incongruence in perceptions of CRs’ decision-making involvement (DMI) and higher level of CR impairment in activities of daily living were significantly related to higher absolute discrepancy between CG and CR about CRs’ QOL. In the logistic models, when the dyad had more DMI incongruence, or CG reported higher relationship strain, the CG was more likely to report a lower CR QOL than CR reported.

Implications:

Practitioners should consider incorporating CRs’ perspective when planning care instead of solely depending on CGs’ perspective. Also, practitioners should pay attention to any gap between perceptions of CGs and CRs, particularly with regard to CRs’ QOL.
Original Research: Central and peripheral quadriceps fatigue in young and middle-aged untrained and endurance-trained men: A comparative study
Authors: Bachasson Damien , Decorte Nicolas , Wuyam Bernard , Millet Guillaume Y , Verges Samuel
Published: June 2016

This study aimed to compare quadriceps function (i.e. strength, endurance, central, and peripheral fatigue) of young (Young-UnTr) and middle-aged (MidAge-UnTr) untrained men and young endurance-trained men (Young-Tr). Twenty-four male subjects (eight Young-UnTr (26 ± 4 yr), eight Young-Tr (29 ± 3 yr), and eight MidAge-UnTr (56 ± 4 yr) performed a maximal cycling test to assess their fitness level. On a separate visit, subjects performed sets of 10 intermittent (5-s on/5-s off) isometric contractions starting at 10% maximum voluntary contraction (MVC), with 10% MVC increments from one set to another until exhaustion. Electrophysiological and mechanical (e.g. twitch) evoked responses elicited with magnetic femoral nerve stimulation in the relaxed muscle and during MVC (i.e . estimation of voluntary activation using the interpolated twitch technique) were measured at baseline and after each set to assess peripheral and central fatigue, respectively. Endurance (= total number of contractions) was also evaluated. Young-UnTr exhibited larger reductions in evoked quadriceps mechanical responses than MidAge-UnTr and Young-Tr after identical standardized muscle loading (e.g. after the 50% MVC set, reduction in single potentiated twitch was −36 ± 9%, −21±16%, and −2 ± 4%, respectively). At both 50% MVC set and exhaustion, MidAge-UnTr exhibited similar reduction in maximal voluntary activation and displayed similar endurance compared to Young-UnTr. Young-Tr exhibited greater endurance than Young-UnTr without significant changes in maximal voluntary activation throughout the test. This study provides robust comparative data regarding the influence of chronic exposure to endurance training and middle-aged on central and peripheral quadriceps fatigability and endurance. Endurance-trained subjects showed smaller level of peripheral fatigue and displayed no significant central fatigue, even at exhaustion and despite greater endurance performance. Our findings also demonstrate that men in the sixth decade exhibit significant alterations in quadriceps function typically observed in much older subjects. These data emphasize the need for developing normative data for both central and peripheral quadriceps fatigability.
Slow Activity in Focal Epilepsy During Sleep and Wakefulness
Authors: Pellegrino Giovanni , Tombini Mario , Curcio Giuseppe , Campana Chiara , Di Pino Giovanni , Assenza Giovanni , Tomasevic Leo , Di Lazzaro Vincenzo
Published: June 2016

Introduction. We aimed to test differences between healthy subjects and patients with respect to slow wave activity during wakefulness and sleep. Methods. Fifteen patients affected by nonlesional focal epilepsy originating within temporal areas and fourteen matched controls underwent a 24-hour EEG recording. We studied the EEG power spectral density during wakefulness and sleep in delta (1-4 Hz), theta (5-7 Hz), alpha (8-11 Hz), sigma (12-15 Hz), and beta (16-20 Hz) bands. Results. During sleep, patients with focal epilepsy showed higher power from delta to beta frequency bands compared with controls. The effect was widespread for alpha band and above, while localized over the affected hemisphere for delta (sleep cycle 1, P = .006; sleep cycle 2, P = .008; sleep cycle 3, P = .017). The analysis of interhemispheric differences showed that the only frequency band stronger over the affected regions was the delta band during the first 2 sleep cycles (sleep cycle 1, P = .014; sleep cycle 2, P = .002). During wakefulness, patients showed higher delta/theta activity over the affected regions compared with controls. Conclusions. Patients with focal epilepsy showed a pattern of power increases characterized by a selective slow wave activity enhancement over the epileptic regions during daytime and sleep. This phenomenon was stronger and asymmetric during the first sleep cycles.
How Different Are the Patients With Bilateral Hippocampal Sclerosis From the Unilateral Ones Clinically?
Authors: Vanli-Yavuz Ebru Nur , Baykan Betul , Sencer Serra , Sencer Altay , Baral-Kulaksizoglu Isin , Bebek Nerses , Gurses Candan , Gokyigit Aysen
Published: June 2016

Purpose. There is a lack of knowledge on consecutive patients with epilepsy associated with bilateral hippocampal sclerosis (BHS). We aimed to investigate the differentiating features of BHS in comparison with unilateral HS (UHS). Method. We investigated our database for patients with epilepsy fulfilling the major magnetic resonance imaging criteria for BHS; namely, presence of bilateral atrophy and high signal changes on T2 and FLAIR series in the hippocampi. UHS patients seen in past 2 years were included as the control group. Clinical, EEG, and other laboratory findings, data on treatment response and epilepsy surgery were investigated from their files. Results. A total of 124 patients (31 with BHS and 93 with UHS; 49 right-sided and 44 left-sided) were included. We found that 16.1% of the BHS and 18.3% of the UHS groups were not drug-refractory. A binary logistic regression analysis performed with significant clinical features disclosed that history of febrile status epilepticus, mental retardation, and status epilepticus were statistically more common in BHS group. Moreover, diagnosis of psychosis established by an experienced psychiatrist and slowing of the EEG background activity were both found significantly more frequent in BHS. 66.67% of the operated BHS patients showed benefit from epilepsy surgery. Conclusions. BHS is a heterogeneous group, showing significant differences such as increased frequencies of mental retardation, status epilepticus, febrile status epilepticus and psychosis, in comparison to UHS. In all, 16.1% of the BHS cases showed a benign course similar to the UHS group and some patients with drug-resistant epilepsy may show benefit from epilepsy surgery.
Intraoperative cone-beam computed tomography contributes to avoiding hypoglossal nerve palsy during transvenous embolization for dural arteriovenous fistula of the anterior condylar confluence
Authors: Okamura Akitake , Nakaoka Mitsuo , Ohbayashi Naohiko , Yahara Kaita , Nabika Shinya
Published: June 2016

Background

Dural arteriovenous fistula of the anterior condylar confluence (ACC-DAVF) is a rare subtype of DAVFs that occurs around the hypoglossal canal. Transvenous embolization (TVE) with coils has been performed for most ACC-DAVFs with a high clinical cure rate. However, some reports call attention to hypoglossal nerve palsy associated with TVE due to coil mass compression of the hypoglossal nerve caused by coil deviation from the ACC to the anterior condylar vein (ACV). Herein, we report a case of ACC-DAVF in which an intraoperative cone-beam computed tomography (CT) contributed to avoiding hypoglossal nerve palsy.

Case presentation

A 74-year-old man presented with left pulse-synchronous tinnitus. An angiography detected left ACC-DAVF mainly supplied by the left ascending pharyngeal artery and mainly drained through the ACV. The two fistulous points were medial side of the ACC and the venous pouch just cranial of the ACC. We performed TVE detecting the fistulous points by contralateral external carotid angiography (ECAG). The diseased venous pouch and ACC were packed with seven coils but a slight remnant of the DAVF was recognized. Because a cone-beam CT revealed that the coil mass was localized in the lateral lower clivus osseous without deviation to the hypoglossal canal, we finished TVE to avoid hypoglossal nerve palsy. Postoperatively, no complication was observed. No recurrence of symptoms or imaging findings were detected during a five-month follow-up period.

Conclusion

An intraoperative cone-beam CT contributed to avoiding hypoglossal nerve palsy by estimating the relationship between the coil mass and the hypoglossal canal during TVE of ACC-DAVF.
Cognitive behavioural therapy
Authors: Chawathey Kunal , Ford Angeliki
Published: June 2016

Cognitive behavioural therapy (CBT) is a psychotherapeutic approach that addresses unhelpful cognitions and behaviours that result in distress. It has been shown to be effective in the management of anxiety disorders, depression, eating disorders, chronic pain syndromes and personality disorders. Although there is a clear need for CBT services, access to them remains limited. GPs cannot be expected to fill this gap, but specific CBT techniques can help in the management of common conditions. In this paper, we will discuss several CBT techniques that a clinician can apply in 10-minute consultations with a case study to espouse how the techniques can be implemented in clinical practice.
H.P. Acthar Gel (repository corticotropin injection) treatment of patients with multiple sclerosis and diabetes
Authors: Kutz Christen
Published: June 2016

Background:

Treatment of multiple sclerosis (MS) relapses can be complex in patients with concomitant diabetes. Corticosteroids and adrenocorticotropic hormones are known to cause alterations in glucose tolerance. Many patients have poor tolerability to therapy, necessitating alternative treatment options. Adrenocorticotropic hormone (H.P. Acthar Gel, repository corticotropin injection, Mallinckrodt ARD Inc., Hazelwood, MO, USA) is currently indicated for the treatment of MS relapses.

Objectives:

The objective of this study was to review patients’ experiences of Acthar Gel for the treatment of MS exacerbations in patients with MS and diabetes.

Methods:

A retrospective review of 13 patients’ experiences with treatment. Qualified healthcare providers completed a questionnaire following Acthar Gel treatment for MS relapse.

Results:

Previous corticosteroid treatment with either intravenous methylprednisolone or prednisone was reported by 84.6% of patients; eight patients had complications following administration of prior steroid treatment, seven of whom experienced elevated blood glucose levels. Acthar Gel was administered daily for a mean of 5.3 days, with 61.5% of patients reporting relapse resolution. Two patients experienced elevated blood glucose.

Conclusion:

The majority of patients experienced a timely resolution of their MS relapse with few hyperglycemic adverse events. Although more studies are necessary, these data suggest that Acthar Gel may be a well-tolerated and effective treatment option for patients with diabetes experiencing an MS relapse.
Developments in Hong Kong Legal Education
Authors: Marsh Luke , Ramsden Michael
Published: June 2016

The history of legal education in Hong Kong is a history of reform. The various inflection points along its story—the establishment of each of the three law schools, the development of the Postgraduate Certificate in Laws (PCLL) and its role in the legal profession, the Redmond–Roper Report and its aftermath—all demonstrate an effort to develop a legal system appropriate to the specific context of Hong Kong. This article traces these developments with a view to providing further insight into ongoing reviews about the structure of legal education in the territory.
Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia
Authors: Metzeler Klaus H. , Herold Tobias , Rothenberg-Thurley Maja , Amler Susanne , Sauerland Maria C. , Görlich Dennis , Schneider Stephanie , Konstandin Nikola P. , Dufour Annika , Bräundl Kathrin , Ksienzyk Bianka , Zellmeier Evelyn , Hartmann Luise , Greif Philipp A. , Fiegl Michael , Subklewe Marion , Bohlander Stefan K. , Krug Utz , Faldum Andreas , Berdel Wolfgang E. , Wörmann Bernhard , Büchner Thomas , Hiddemann Wolfgang , Braess Jan , Spiekermann Karsten
Published: June 2016

The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients.
A longitudinal study characterising a large adult primary ciliary dyskinesia population
Authors: Shah Anand , Shoemark Amelia , MacNeill Stephanie J. , Bhaludin Basrull , Rogers Andrew , Bilton Diana , Hansell David M. , Wilson Robert , Loebinger Michael R.
Published: June 2016

Primary ciliary dyskinesia (PCD) in adults has not been well described. In this retrospective observational study we aimed to characterise a large adult population and identify features associated with disease progression.

We retrospectively analysed 151 adult patients at a single tertiary centre at baseline and longitudinally for a median of 7 years.

We found significant variation in age at diagnosis (median 23.5 years; range <1–72 years). Older age at diagnosis was associated with impaired baseline forced expiratory volume in 1 s (FEV1) (r= −0.30, p=0.01) and increasedPseudomonas aeruginosacolonisation (difference in medians 17 years (95% CI 4.5–20 years); p=0.002). Lung function decline was estimated at FEV1decline of 0.49% predicted per year. Lung function decline was associated with ciliary ultrastructure, with microtubular defect patients having the greatest decline (p=0.04). High-resolution computed tomography (HRCT) scores of severity of bronchial wall dilatation (p<0.001) and extent of bronchiectasis (p=0.03) additionally showed evidence of modifying FEV1decline with age.

Our study reveals that a large proportion of adult PCD patients are diagnosed late, with impaired FEV1and increasedP. aeruginosacolonisation. Increased disease burden on HRCT and ciliary ultrastructure may predict progressive lung function decline. This study characterises a large adult PCD population, identifies features associated with disease progression and highlights the need for prospective trials to determine whether early diagnosis of high-risk subgroups alongside optimal management can modify disease progression.
Comparison of NHANES III and ERS/GLI 12 for airway obstruction classification and severity
Authors: Linares-Perdomo Olinto , Hegewald Matthew , Collingridge Dave S. , Blagev Denitza , Jensen Robert L. , Hankinson John , Morris Alan H.
Published: June 2016

The diagnosis and severity categorisation of obstructive lung disease is determined using reference values. The American Thoracic Society/European Respiratory Society in 2005 recommended the National Health and Nutrition Examination Survey (NHANES) III spirometry prediction equations for patients in USA aged 8–80 years. The Global Lung Initiative 2012 (GLI 12) provided spirometry prediction equations for patients aged 3–95 years. Comparison of the NHANES III and GLI 12 prediction equations for diagnosing and categorising airway obstruction in patients in USA has not been made.

We aimed to quantify the differences between NHANES III and GLI 12 predicted values in Caucasians aged 18–95 years, using both mathematical simulation and clinical data. We compared predicted forced expiratory volume in 1 s (FEV1) and lower limit of normal (LLN) FEV1/forced vital capacity (FVC) % for NHANES III and GLI 12 prediction equations by applying both a simulation model and clinical spirometry data to quantify differences in the diagnosis and categorisation of airway obstruction.

Mathematical simulation revealed significant similarities and differences between prediction equations for both LLN FEV1/FVC % and predicted FEV1. There are significant differences when using GLI 12 and NHANES III to diagnose airway obstruction and severity in Caucasian patients aged 18–95 years.

Similarities and differences exist between NHANES III and GLI 12 for some age and height combinations. The differences in LLN FEV1/FVC % and predicted FEV1are most prominent in older taller/shorter individuals. The magnitude of the differences can be large and may result in differences in clinical management.
Attrition of memory CD8 T cells during sepsis requires LFA-1
Authors: Serbanescu Mara A , Ramonell Kimberly M , Hadley Annette , Margoles Lindsay M , Mittal Rohit , Lyons John D , Liang Zhe , Coopersmith Craig M , Ford Mandy L , McConnell Kevin W
Published: June 2016

CD8 T cell loss and dysfunction have been implicated in the increased susceptibility to opportunistic infections during the later immunosuppressive phase of sepsis, but CD8 T cell activation and attrition in early sepsis remain incompletely understood. With the use of a CLP model, we assessed CD8 T cell activation at 5 consecutive time points and found that activation after sepsis results in a distinct phenotype (CD69+CD25intCD62LHI) independent of cognate antigen recognition and TCR engagement and likely through bystander-mediated cytokine effects. Additionally, we observed that sepsis concurrently results in the preferential depletion of a subset of memory-phenotype CD8 T cells that remain “unactivated” (i.e., fail to up-regulate activation markers) by apoptosis. Unactivated CD44HI OT-I cells were spared from sepsis-induced attrition, as were memory-phenotype CD8 T cells of mice treated with anti-LFA-1 mAb, 1 h after CLP. Perhaps most importantly, we demonstrate that attrition of memory phenotype cells may have a pathologic significance, as elevated IL-6 levels were associated with decreased numbers of memory-phenotype CD8 T cells in septic mice, and preservation of this subset after administration of anti-LFA-1 mAb conferred improved survival at 7 d. Taken together, these data identify potentially modifiable responses of memory-phenotype CD8 T cells in early sepsis and may be particularly important in the application of immunomodulatory therapies in sepsis.
Cost-Effectiveness Analysis of Different Sequences of the Use of Epidermal Growth Factor Receptor Inhibitors for Wild-Type KRAS Unresectable Metastatic Colorectal Cancer
Authors: Riesco-Martínez Maria Carmen , Berry Scott R. , Ko Yoo-Joung , Mittmann Nicole , Giotis Angie , Lien Kelly , Wong William W.L. , Chan Kelvin K.W.
Published: June 2016

Purpose:

Patients with unresectable wild-type KRAS metastatic colorectal cancer benefit from fluoropyrimidines (FP), oxaliplatin (O), irinotecan (I), bevacizumab (Bev), and epithelial growth factor receptor inhibitors (EGFRI). The most cost-effective regimen remains unclear.

Methods:

A Markov model was constructed to examine the costs and outcomes of three treatment strategies: strategy A (reference strategy): EGFRI monotherapy in third line ([3L]; ie, first-line [1L]: Bev + FOLFIRI [FP + I] or FOLFOX [FP + O]; second line [2L]: FOLFIRI/FOLFOX; 3L: EGFRI); strategy B: EGFRI and I in 3L (ie, 1L: Bev + FOLFIRI/FOLFOX; 2L: FOLFIRI/FOLFOX; 3L: EGFRI + I); and strategy C: EGFRI in 1L (ie, 1L: EGFRI + FOLFIRI/FOLFOX; 2L: Bev + FOLFIRI/FOLFOX; 3L: best supportive care). Efficacy data of the treatments were obtained from the literature. Health system resource use information was derived from chart review and the literature. Using Euro-QOL 5 Dimensions, utilities were obtained by surveying medical oncologists and costs from the Ontario Ministry of Health and the literature. The perspective of the Canadian public health care system was used over a 5-year time horizon with a 5% discount in 2012 Canadian dollars.

Results:

All three strategies had similar efficacy, but strategy C was most expensive. The incremental cost-effectiveness ratios (ICERs) for strategies B and C compared with A were 119,623 and 3,176,591, respectively. The model was primarily driven by the acquisition cost of the drugs. Strategy B was most cost effective when the willingness-to-pay threshold was > $130,000 per quality-adjusted life-year. Sensitivity analysis showed that strategy C would be cost-effective only when the progression-free survival of EGFRI is better than Bev in 1L with hazard ratio < 0.23 at willingness-to-pay of $150,000 per quality-adjusted life-year.

Conclusion:

First-line use of EGFRI in metastatic colorectal cancer is not cost effective at its current pricing relative to Bev.
Use of Gene Expression Profiling and Chemotherapy in Early-Stage Breast Cancer: A Study of Linked Electronic Medical Records, Cancer Registry Data, and Genomic Data Across Two Health Care Systems
Authors: Afghahi Anosheh , Mathur Maya , Thompson Caroline A. , Mitani Aya , Rigdon Joseph , Desai Manisha , Yu Peter P. , de Bruin Monique A. , Seto Tina , Olson Cliff , Kenkare Pragati , Gomez Scarlett L. , Das Amar K. , Luft Harold S. , Sledge George W. , Sing Amy P. , Kurian Allison W.
Published: June 2016

Purpose:

The 21-gene recurrence score (RS) identifies patients with breast cancer who derive little benefit from chemotherapy; it may reduce unwarranted variability in the use of chemotherapy. We tested whether the use of RS seems to guide chemotherapy receipt across different cancer care settings.

Methods:

We developed a retrospective cohort of patients with breast cancer by using electronic medical record data from Stanford University (hereafter University) and Palo Alto Medical Foundation (hereafter Community) linked with demographic and staging data from the California Cancer Registry and RS results from the testing laboratory (Genomic Health Inc., Redwood City, CA). Multivariable analysis was performed to identify predictors of RS and chemotherapy use.

Results:

In all, 10,125 patients with breast cancer were diagnosed in the University or Community systems from 2005 to 2011; 2,418 (23.9%) met RS guidelines criteria, of whom 15.6% received RS. RS was less often used for patients with involved lymph nodes, higher tumor grade, and age < 40 or ≥ 65 years. Among RS recipients, chemotherapy receipt was associated with a higher score (intermediate v low: odds ratio, 3.66; 95% CI, 1.94 to 6.91). A total of 293 patients (10.6%) received care in both health care systems (hereafter dual use); although receipt of RS was associated with dual use (v University: odds ratio, 1.73; 95% CI, 1.18 to 2.55), there was no difference in use of chemotherapy after RS by health care setting.

Conclusion:

Although there was greater use of RS for patients who sought care in more than one health care setting, use of chemotherapy followed RS guidance in University and Community health care systems. These results suggest that precision medicine may help optimize cancer treatment across health care settings.
Pathways Clinical Decision Support for Appropriate Use of Key Biomarkers
Authors: Ellis Peter G. , Brufsky Adam M. , Beriwal Sushil , Lokay Kathleen G. , Benson Hans O. , McCutcheon Stephanie B. , Krebs Melinda
Published: June 2016

Purpose:

Breast cancer diagnostics have the ability to predict disease recurrence and the benefit of chemotherapy. This study measures the use of a diagnostic assay, Oncotype DX, when embedded in a breast cancer decision support algorithm and, on the basis of the assay results, the use of chemotherapy in the adjuvant setting.

Methods:

UPMC CancerCenter retrospectively reviewed patients with estrogen receptor–positive, human epidermal growth factor receptor 2 (HER2)Neu–negative disease with zero to three positive nodes navigated in the Via Pathways decision support portal during a 12-month period. The breast algorithm prompted input of the assay recurrence score (RS) and then recommended hormonal therapy alone (HT) for low RS, or chemotherapy followed by HT for high RS. The patient’s RS was correlated with the treatment decision.

Results:

During this time period, 643 patients had ER-positive, HER2Neu-negative disease with zero to three positive nodes. Of those, 596 (92.7%) had diagnostic testing to determine chemotherapy plus HT versus HT alone, and 47 had chemotherapy followed by HT without an RS. For node-negative patients classified with low or high RS, pathway treatment adherence rates were 99.7% and 96.6%, respectively; node-positive patients had 95.7% and 87.5% adherence rates, respectively.

Conclusion:

This analysis demonstrates the use of a clinical pathway to measure the adoption of a diagnostic test, the Oncotype DX breast assay, and the use of the appropriate therapy on the basis of the RS. As more diagnostics are established to aid in the personalized treatment of diseases, pathways may be important in maintaining clinician awareness of the appropriate disease presentations where these tests should be used, measuring usage of these tests, and tracking the treatment decisions on the basis of test results.
Clinical Benefits Associated With Medicaid Coverage Before Diagnosis of Gynecologic Cancers
Authors: Doll Kemi M. , Basch Ethan M. , Meng Ke , Barber Emma L. , Gehrig Paola A. , Brewster Wendy R. , Meyer Anne-Marie
Published: June 2016

Purpose:

Many low-income patients enroll in Medicaid at the time of cancer diagnosis, which improves survival outcomes. Medicaid enrollment before cancer diagnosis may confer additional benefits. Our objective was to compare stage at diagnosis and overall mortality between women with and without Medicaid enrollment before gynecologic cancer diagnosis.

Methods and Materials:

Women younger than 65 years with a gynecologic cancer (2003 to 2008) were identified through the North Carolina Central Cancer Registry and linked to state Medicaid enrollment files. Those with and without Medicaid enrollment within 6 months before diagnosis were identified. Propensity matching was used to balance the exposure groups. Stage at diagnosis was evaluated by using logistic regression, and all-cause mortality was assessed with Cox proportional hazard models.

Results:

Of 564 women, one half (n = 282) had prediagnosis Medicaid enrollment. Disease sites included the cervix (44%), uterus (25%), ovary (26%), and vulva/vagina (5%). More than one half (51%) of cancers were advanced stage. Women without prediagnosis Medicaid had an increased odds of advanced-stage disease (hazard ratio, 1.46; 95% CI, 1.03 to 2.05). Crude survival outcomes differed significantly between the groups; however, when adjusted for stage at diagnosis, lack of prediagnosis Medicaid coverage had a hazard ratio of 1.19 (95% CI, 0.92 to 1.53).

Conclusion:

Medicaid enrollment before gynecologic cancer diagnosis is associated with an earlier stage at presentation. Given the existence of a cervical cancer screening program in North Carolina and lack of Medicaid expansion, these data suggest that screening programs alone are not sufficient to counteract the delay in diagnosis that is common for uninsured individuals.
Management of Brain Metastases in Patients With Melanoma
Authors: Chukwueke Ugonma , Batchelor Tracy , Brastianos Priscilla
Published: June 2016

Melanoma is the third most common systemic cancer that leads to brain metastases. The annual incidence of melanoma has increased over time, with brain metastases developing in 40% to 50% of patients with advanced melanoma. Traditional management of melanoma-related brain metastases has focused on symptom control as a result of the significant neurologic morbidity associated with the disease. Median overall survival for these patients, if untreated, is approximately 3 months. As with other brain metastases, a multidisciplinary treatment approach that includes surgery and radiation therapy is typically used, with historically little role for systemic, cytotoxic therapy. During the past decade, advancement within the field of genomics has led to the identification of melanoma-specific mutations, namely, v-Raf murine sarcoma viral oncogene homolog B and neuroblastoma RAS viral oncogene homolog, as well as to the development of agents that target these driver mutations. In addition, the advent of immunotherapies, specifically, agents that target cytotoxic T-lymphocyte antigen-4, anti–programmed death-1, and programmed death ligand-1, has increased the potential therapeutic options available to patients with both systemic and brain disease. With these advances, early trials have demonstrated improved overall survival in patients with brain metastases who receive these therapies either as single agents or as part of multimodality treatment regimens.
Microangiopathic Hemolytic Anemia and Thrombocytopenia in Patients With Cancer
Authors: Morton Jordan M. , George James N.
Published: June 2016

The unexpected occurrence of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia and thrombocytopenia, in a patient with cancer requires urgent diagnosis and appropriate management. TMA is a term used to describe multiple syndromes caused by microvascular thrombosis, including thrombotic thrombocytopenic purpura (TTP), Shiga toxin–mediated hemolytic uremic syndrome, and complement-mediated TMA. In patients with cancer, systemic microvascular metastases and bone marrow involvement can cause microangiopathic hemolytic anemia and thrombocytopenia. This occurs most often in patients with known metastatic cancer, but microangiopathic hemolytic anemia and thrombocytopenia may occur unexpectedly in patients without known metastatic disease or be the presenting features of undiagnosed cancer. TMA may also be caused by commonly used chemotherapy agents, either through dose-dependent toxicity or an acute immune-mediated reaction. These causes of TMA must be distinguished from TTP, which results from a severe deficiency of ADAMTS13 and is the most common cause of TMA among adults without cancer. The importance of this distinction is to avoid inappropriate use of plasma exchange, which is associated with major complications. Plasma exchange is the essential treatment for TTP, but it has no known benefit for patients with cancer-induced or drug-induced TMA. We will describe cancer-induced and drug-induced TMA using the experience of the Oklahoma TTP–Hemolytic Uremic Syndrome Registry and data from a systematic review of all published reports of drug-induced TMA. We will illustrate the principles of evaluation and management of these disorders with patients’ stories.
Proteomic analysis reveals APC-dependent post translational modifications and identifies a novel regulator of β-catenin
Authors: Blundon Malachi A. , Schlesinger Danielle R. , Parthasarathy Amritha , Smith Samantha L. , Kolev Hannah M. , Vinson David A. , Kunttas-Tatli Ezgi , McCartney Brooke M. , Minden Jonathan S.
Published: June 2016

Wnt signaling generates patterns in all embryos, from flies to humans, and controls cell fate, proliferation, and metabolic homeostasis. Inappropriate Wnt pathway activation results in diseases, including colorectal cancer. The Adenomatous polyposis coli (APC) tumor suppressor gene encodes a multifunctional protein that is an essential regulator of Wnt signaling and cytoskeletal organization. While progress has been made in defining the role of APC in a normal cellular context, there are still significant gaps in our understanding of APC-dependent cellular function and dysfunction. We expanded the APC-associated protein network using a combination of genetics and a proteomic technique called Two-dimensional Difference Gel Electrophoresis (2D-DIGE). We show that loss of APC2 causes protein isoform changes reflecting misregulation of post-translational modifications (PTMs), which are not dependent on β-cat transcriptional activity. Mass spectrometry revealed that proteins involved in metabolic and biosynthetic pathways, protein synthesis and degradation, and cell signaling are affected by the loss of APC2. We demonstrate that changes in phosphorylation partially account for the altered PTMs in APC mutants, suggesting that APC mutants affect other types of PTM. Finally, through this approach Aminopeptidase P was identified as a new regulator of β-catenin abundance in Drosophila embryos. This study provides new perspectives on APC's cellular effects that may lead to a richer understanding of APC's role in development.
Inhibition of β-catenin signalling in dermal fibroblasts enhances hair follicle regeneration during wound healing
Authors: Rognoni Emanuel , Gomez Celine , Pisco Angela Oliveira , Rawlins Emma L. , Simons Ben D. , Watt Fiona M. , Driskell Ryan R.
Published: June 2016

New hair follicles (HF) do not form in adult mammalian skin unless epidermal Wnt signalling is activated genetically or within large wounds. To understand the postnatal loss of hair forming ability we made small (2mm diameter) circular wounds and monitored HF formation at the wound site. At P2 new follicles formed in back skin, but follicle formation was markedly decreased by P21. Neonatal tail also formed wound-associated follicles, albeit in smaller numbers. Postnatal loss of HF neogenesis did not correlate with wound closure rate but with reduction in Lrig1-positive papillary fibroblasts in wounds. Comparative gene expression profiling of back and tail dermis at P1 and dorsal fibroblasts at P2 and P50 showed a correlation between loss of HF formation and decreased expression of genes associated with proliferation and Wnt/β-catenin activity. Between P2 and P50 fibroblast density declined throughout the dermis and clones of fibroblasts became more dispersed. This correlated with a decline in fibroblasts expressing a TOPGFP reporter of Wnt activation. Surprisingly, between P2 and P50 there was no difference in fibroblast proliferation at the wound site but Wnt signalling was highly upregulated in healing dermis of P21 compared to P2 mice. Postnatal β-catenin ablation in fibroblasts promoted HF regeneration in neonatal and adult mouse wounds while β-catenin activation reduced HF regeneration in neonatal wounds. Our data support a model whereby postnatal loss of hair forming ability in wounds reflects elevated dermal Wnt/β-catenin activation in the wound bed, increasing the abundance of fibroblasts that are unable to induce HF formation.
Eph-ephrin signaling maintains the boundary of dorsal forerunner cell cluster during morphogenesis of the zebrafish embryonic left-right organizer
Authors: Zhang Jun-Feng , Jiang Zheng , Liu Xingfeng , Meng Anming
Published: June 2016

The kupffer's vesicle (KV) is the so-called left-right organizer in teleost fishes. KV is formed from dorsal forerunner cells (DFCs) and generates asymmetrical signals for breaking symmetry of embryos. It is unclear how DFCs or KV cells are prevented from intermingling with adjacent cells. In this study, we show that the Eph receptor gene ephb4b is highly expressed in DFCs while the ephrin ligand genes including efnb2b are expressed in cells next to the DFCs cluster during zebrafish gastrulation. ephb4b knockdown or mutation and efnb2b knockdown cause dispersal of DFCs, a smaller KV and randomization of laterality organs. The DFCs often dynamically form lamellipodium-like, bleb-like and filopodium-like membrane protrusions at the interface, which attempt to invade but are bounced back by adjacent non-DFC cells during gastrulation. Upon inhibition of Eph-ephrin signaling, however, the repulsion between DFCs and non-DFC cells is weakened or lost, allowing DFCs to migrate away. Ephb4b/efnb2b signaling by activating RhoA activity mediates contact and repulsion between DFCs and neighboring cells during gastrulation, preventing intermingling of different cell populations. Therefore, our data uncover an important role of Eph/ephrin signaling in maintaining DFCs boundary and KV boundary for normal left-right asymmetrical development.
A distal 594bp ECR specifies Hmx1 expression in pinna and lateral facial morphogenesis and is regulated by Hox-Pbx-Meis
Authors: Rosin Jessica M. , Li Wenjie , Cox Liza L. , Rolfe Sara M. , Latorre Victor , Akiyama Jennifer A. , Visel Axel , Kuramoto Takashi , Bobola Nicoletta , Turner Eric E. , Cox Timothy C.
Published: June 2016

Hmx1 encodes a homeodomain transcription factor expressed in the developing lateral craniofacial mesenchyme, retina and sensory ganglia. Mutation or mis-regulation of Hmx1 underlies malformations of the eye and external ear in multiple species. Deletion or insertional duplication of an evolutionarily conserved region (ECR) downstream of Hmx1 has recently been described in rat and cow, respectively. Here we demonstrate the impact of Hmx1 loss is greater than previously appreciated, with a variety of lateral cranioskeletal defects, auriculofacial nerve deficits, and duplication of the caudal region of the external ear. Using a transgenic approach, we demonstrate that a 594bp sequence encompassing the ECR recapitulates specific aspects of the endogenous Hmx1 lateral facial expression pattern. Moreover, we show that Hoxa2, Meis and Pbx act cooperatively on the ECR, via a core 32bp sequence, to regulate Hmx1 expression. These studies highlight the conserved role for Hmx1 in BA2-derived tissues and provide an entry point to better understand the causes of the frequent lateral facial birth defects in humans.