bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-HER Inhibitor Augments Radiation Response in Human Lung and Head and Neck Cancer Models
Authors: Francis David M. , Huang Shyhmin , Armstrong Eric A. , Werner Lauryn R. , Hullett Craig , Li Chunrong , Morris Zachary S. , Swick Adam D. , Kragh Michael , Lantto Johan , Kimple Randall J. , Harari Paul M. 
Published: September 2015

Abstract
Purpose: Aberrant regulation of the EGF receptor family (EGFR, HER2, HER3, HER4) contributes to tumorigenesis and metastasis in epithelial cancers. Pan-HER represents a novel molecular targeted therapeutic composed of a mixture of six monoclonal antibodies against EGFR, HER2, and HER3.
Experimental Design: In the current study, we examine the capacity of Pan-HER to augment radiation response across a series of human lung and head and neck cancers, including EGFR inhibitor–resistant cell lines and xenografts.
Results: Pan-HER demonstrates superior antiproliferative and radiosensitizing impact when compared with cetuximab. The mechanisms underlying these effects appear to involve attenuation of DNA damage repair, enhancement of programmed cell death, cell-cycle redistribution, and induction of cellular senescence. Combined treatment of Pan-HER with single or fractionated radiation in human tumor xenografts reveals a potent antitumor and regrowth delay impact compared with Pan-HER or radiation treatment alone.
Conclusions: These data highlight the capacity of Pan-HER to augment radiation response in lung and head and neck cancer models and support investigation of Pan-HER combined with radiation as a promising clinical therapeutic strategy. Clin Cancer Res; 22(3); 633–43. ©2015 AACR.
Subacute CNS Demyelination after Treatment with Nivolumab for Melanoma
Authors: Maurice Catherine , Schneider Raphael , Kiehl Tim-Rasmus , Bavi Prashant , Roehrl Michael H.A. , Mason Warren P. , Hogg David 
Published: September 2015

Abstract
Immunotherapy with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) has improved the survival of patients with metastatic melanoma. These agents carry a certain risk of adverse immune-related events. We present a patient with widely metastatic melanoma who was initially treated with ipilimumab and subsequently with nivolumab. After four infusions of nivolumab, he developed subacute multifocal central nervous system (CNS) demyelination. Nivolumab was discontinued and, despite immunosuppressive therapy, the largest lesion progressed significantly, whereas another lesion showed radiographic improvement. After further progression, the patient succumbed to his CNS lesions 4 months later. Autopsy revealed extensive demyelination, a mild multifocal T-cell–rich perivascular lymphoid infiltrate, abundant macrophages, and necrosis. There was no metastatic melanoma in the brain. CNS demyelination has not been described in association with nivolumab. We hypothesize that the combination therapy of ipilimumab and subsequent nivolumab accounted for the severity of the demyelinating process in this patient. This case, with comprehensive clinical, molecular, and neuropathologic characterization, illustrates the need for awareness of these potential CNS complications with the use of multiple checkpoint inhibitors. Cancer Immunol Res; 3(12); 1299–302. ©2015 AACR.
Proteolytically active ADAM10 and ADAM17 carried on membrane microvesicles in human abdominal aortic aneurysms
Authors: Li Chunjun , Frebelius Siw , Swedenborg Jesper , Wågsäter Dick , Williams Kevin Jon , Eriksson Per , Folkesson Maggie , Roy Joy , Liu Ming-Lin 
Published: September 2015

SummaryThe intraluminal thrombus (ILT) of human abdominal aortic aneurysm (AAA) has been suggested to damage the underlying aortic wall, but previous work found scant activity of soluble proteases in the abluminal layer of the ILT, adjacent to the aneurysm. We hypothesised that transmembrane proteases carried by membrane microvesicles (MV) from dying cells remain active in the abluminal ILT. ILTs and AAA segments collected from 21 patients during surgical repair were assayed for two major transmembrane proteases, ADAM10 (a disintegrin and metalloprotease-10) and ADAM17. We also exposed cultured cells to tobacco smoke and assessed ADAM10 and ADAM17 expression and release on MVs. Immunohistochemistry showed abundant ADAM10 and ADAM17 protein in the ILT and underlying aneurysmal aorta. Domain-specific antibodies indicated both transmembrane and shed ADAM17. Importantly, ADAM10 and ADAM 17 in the abluminal ILT were enzymatically active. Electron microscopy of abluminal ILT and aortic wall showed MVs with ADAM10 and ADAM17. By flow cytometry, ADAM-positive microvesicles from abluminal ILT carried the neutrophil marker CD66, but not the platelet marker CD61. Cultured HL60 neutrophils exposed to tobacco smoke extract showed increased ADAM10 and ADAM17 content, cleavage of these molecules into active forms, and release of MVs carrying mature ADAM10 and detectable ADAM17. In conclusion, our results implicate persistent, enzymatically active ADAMs on MVs in the abluminal ILT, adjacent to the aneurysmal wall. The production of ADAM10- and ADAM17-positive MVs from smoke-exposed neutrophils provides a novel molecular mechanism for the vastly accelerated risk of AAA in smokers.Portions of this work were presented at the Arteriosclerosis, Thrombosis and Vascular Biology 2012 Scientific Sessions, 19 Apr 2012 (ref. 25), and in a doctoral thesis defense February 2013 (ref. 26).
Time trends and case fatality rate of in-hospital treated pulmonary embolism during 11 years of observation in Northwestern Italy
Authors: Ageno Walter , Pomero Fulvio , Fenoglio Luigi , Squizzato Alessandro , Bonzini Matteo , Dentali Francesco 
Published: September 2015

SummaryPulmonary embolism (PE) is a common disorder with high mortality and morbidity rates. However, population-based information on its incidence and prognosis remains limited. We conducted a large epidemiology study collecting data on hospitalisation for PE (from 2002 to 2012) in a population of about 13 million people in Northwestern Italy. Patients were identified using the ICD-9-CM codes: 415.11, 415.19; gender and age specific incidence rate of PE during the study period were estimated using the resident population for each year of the study. Furthermore, time trends in the in-hospital PE-related mortality and case fatality rate were calculated. Results were adjusted for possible confounders. A total of 60,853 patients (mean age 72.8 years, ± 14.1, 59.6 % females) with PE were included; the overall crude incidence rate for the entire study period was 55.4 and 40.6 events per year per 100,000 inhabitants for women and men, respectively (p < 0.001). However, this difference was completely lost after standardisation for age. The incidence of PE significantly increased in both genders during the study period. In-hospital case fatality rate significantly decreased throughout the study period (p < 0.001) in women (from 15.6 % to 10.2 %) and in men (from 17.6 % to 10.1 %). The observed decrease of the in-hospital case-fatality throughout the study period remained significant also after adjustment for possible confounders. In conclusion, time trends over an 11-year period show an increasing incidence of PE, but a significant reduction in mortality during hospitalisation. Reduction in the case fatality rate remained significant after adjustment for these possible confounders.Supplementary Material to this article is available online at www.thrombosis-online.com.
Development and validation of a tool for patient reporting of symptoms and signs of the post-thrombotic syndrome
Authors: Utne Kristin Kornelia , Ghanima Waleed , Foyn Siv , Kahn Susan , Sandset Per Morten , Wik Hilde Skuterud 
Published: September 2015

SummaryPost-thrombotic syndrome (PTS) is a long-term complication of deepvein thrombosis (DVT). The Villalta scale is the recommended tool for diagnosing PTS, but requires a clinician’s assessment in addition to patient self-assessment. In the present study, we validated a self-administered tool for patient reporting of leg symptoms and signs as a mean to assess PTS. We first validated a form for patient self-reported Villalta (PRV1), then developed and validated a visually assisted form (PRV2). The validity of PRV1 and PRV2 was assessed in patients diagnosed with DVT between 2004 and 2012. Median time from DVT to inclusion was 5.1 and 3.5 years for PRV1 (n=162) and PRV2 (n=94), respectively. Patients were requested to complete the PRV form before a scheduled visit. PTS diagnosed by the original Villalta scale during the visit served as the reference method. PRV1 showed only moderate agreement for diagnosing PTS compared with the original Villalta scale (kappa agreement 0.60, 95 % CI 0.48–0.72), whereas PRV2 showed very good agreement (0.82, 95 % CI 0.71–0.94). In the validation of PRV2, PTS was diagnosed in 54 (57 %) patients according to the original Villalta scale and in 60 (64 %) by PRV2. The sensitivity of PRV2 to detect PTS was 98 % and the specificity was 83 %. We conclude that the visually assisted form for PRV is a valid and sensitive tool for diagnosing PTS. Such a tool could be applied in further clinical studies of PTS, making studies less resource demanding by reducing the need for in-person clinic visits.Supplementary Material to this article is available online at www.thrombosis-online.com.
Poor Collateral Circulation Assessed by Multiphase Computed Tomographic Angiography Predicts Malignant Middle Cerebral Artery Evolution After Reperfusion Therapies
Authors: Flores Alan , Rubiera Marta , Ribó Marc , Pagola Jorge , Rodriguez-Luna David , Muchada Marian , Boned Sandra , Seró Laia , Sanjuan Estela , Meler Pilar , Carcámo Daniel , Santamarina Estevo , Tomassello Alejandro , Lemus Miguel , Coscojuela Pilar , Molina Carlos A. 
Published: September 2015

Background and Purpose—
Collateral circulation (CC) has been associated with recanalization, infarct volume, and clinical outcome in patients undergoing acute reperfusion therapies. However, its relationship with the development to malignant middle cerebral artery infarction (mMCAi) has not been evaluated. Our aim was to determine the impact of CC using multiphase computed tomographic angiography (during the acute stroke phase in the prediction of mMCAi.

Methods—
Patients with consecutive acute stroke with <4.5 hours who were evaluated for reperfusion therapies and presented with an M1-MCA or terminal internal carotid artery occlusion by CTA were included. CC was evaluated on 6 grades by multiphase CTA according to the University of Calgary CC Scale; CC status was defined as poor (grades, 0–3) or good (grades, 4–5). The mMCAi was defined according to clinical and radiological criteria. Recanalization was assessed with transcranial Doppler at 24 hours and final Thrombolysis in Brain Ischemia score ≥2b in patients undergoing endovascular reperfusion treatment.

Results—

Eighty-two patients were included. Mean age was 65.1±13.83 years, median baseline National Institutes of Health Stroke Scale score was 18 (interquartile range, 13–20), and 67.9% M1 and 32.1% terminal internal carotid artery occlusions. Fifty-three patients received endovascular reperfusion treatment. Fifteen patients developed mMCAi. In the univariate analysis, patients with mMCAi had lower CC scores (2.29 versus 3.71;
P
=0.001). Endovascular reperfusion treatment was associated with lower rate of mMCAi development than only intravenous reperfusion treatment (9.4% versus 29.6%;
P
=0.028). Patients with poor CC had higher risk of developing mMCAi (13% versus 2%;
P
=0.001). On the multivariate analysis adjusted by age, vessel occlusion, baseline National Institutes of Health Stroke Scale, and recanalization, the presence of poor CC by multiphase CTA was the only independent predictor of mMCAi (
P
=0.048; odds ratio, 9.72; 95% confidence interval, 1.387–92.53).

Conclusions—
CC assessment by multiphase CTA independently predicts malignant MCA infarction progression. In patients with persistent occlusion after reperfusion therapies, the presence of poor CC may improve the early mMCAi detection and management.
2015 Bernhard Haurwitz Memorial Lecture: Model Diagnosis of El Niño Teleconnections to the Global Atmosphere–Ocean System
Authors: Lau Ngar-Cheung 
Published: September 2015

Abstract
The El Niño–Southern Oscillation (ENSO) phenomenon is one of the most prominent modes of atmospheric and oceanic variability on interannual and interdecadal time scales. The essential ENSO signals originate from the tropical Pacific (TP). However, the impacts of ENSO are felt in many other parts of the world. Major ENSO events are accompanied by notable changes in the extratropical atmospheric circulation in both hemispheres, various monsoon systems located beyond the TP, global air temperature and precipitation patterns, and the sea surface temperature (SST) distribution throughout the World Ocean. During the past several decades, this author has participated in a sustained effort to study the processes contributing to these “teleconnections” between ENSO forcing in the TP and variations in the atmosphere–ocean system elsewhere. These investigations are based on a large suite of experiments with several generations of general circulation models (GCMs) at the Geophysical Fluid Dynamics Laboratory (GFDL). These experiments are specifically designed to reveal various facets of the teleconnections with ENSO. In this lecture, a summary is given of the principal findings of this series of model studies. An account is given of the train of thought underpinning the sequence of experiments described herein, so as to illustrate how certain experimental setups have been motivated by the problem or hypothesis at hand.
Numerical Simulations of Typhoon Morakot (2009) Using a Multiply Nested Tropical Cyclone Prediction Model
Authors: Hendricks Eric A. , Jin Yi , Moskaitis Jonathan R. , Doyle James D. , Peng Melinda S. , Wu Chun-Chieh , Kuo Hung-Chi 
Published: September 2015

Abstract
High-impact Typhoon Morakot (2009) was investigated using a multiply nested regional tropical cyclone prediction model. In the numerical simulations, the horizontal grid spacing, cumulus parameterizations, and microphysical parameterizations were varied, and the sensitivity of the track, intensity, and quantitative precipitation forecasts (QPFs) was examined. With regard to horizontal grid spacing, it is found that convective-permitting (5 km) resolution is necessary for a reasonably accurate QPF, while little benefit is gained through the use of a fourth domain at 1.67-km horizontal resolution. Significant sensitivity of the track forecast was found to the cumulus parameterization, which impacted the model QPFs. In particular, the simplified Arakawa–Schubert parameterization tended to erroneously regenerate the remnants of Tropical Storm Goni to the southwest of Morakot, affecting the large-scale steering flow and the track of Morakot. Strong sensitivity of the QPFs to the microphysical parameterization was found, with the track and intensity showing little sensitivity. It is also found that Morakot’s accumulated precipitation was reasonably predictable, with the control simulation producing an equitable threat score of 0.56 for the 3-day accumulated precipitation using a threshold of 500 mm. This high predictability of precipitation is due in part to more predictable large-scale and topographic forcing.
Mindfulness-based stress reduction for long-term physical conditions: A systematic review
Authors: Crowe Marie , Jordan Jennifer , Burrell Beverley , Jones Virginia , Gillon Deborah , Harris Shirley 
Published: September 2015

Objective: To identify whether mindfulness-based stress reduction is effective in improving physical health outcomes for long-term physical conditions. Method: A systematic review of the literature (retrieved from MEDLINE, PubMed and PsycINFO). Results: Fifteen studies were included in the review. None of the studies assessed as having a low risk of bias demonstrated significant improvements in physical health status although there was some emerging evidence that mindfulness-based stress reduction may be useful in pain conditions. There was some preliminary evidence that it may also be effective in improving primary insomnia and irritable bowel syndrome. Small to moderate effect sizes were also found for asthma, pain, tinnitus, fibromyalgia and somatization disorders. Conclusion: Although there is some preliminary support for the use of mindfulness-based stress reduction in physical health conditions, further research is required before it could be considered an effective intervention for improving physical health outcomes.
The managerial conversion of senior civil servants: a convenient myth for the French local welfare state?
Authors: Alcaras Jean-Robert , Marrel Guillaume , Marchand Christèle , Nonjon Magali 
Published: September 2015

Has New Public Management really been rolled out homogenously across the board? Drawing on research into the viewpoints and practices of a particular category of senior civil servants in France (those in charge of local welfare policy), this article takes a critical look at this assumption of convergence towards NPM. Behind a discursive convergence that remains superficial and partial, the reality tends more towards heterogeneous and contextualized appropriations of New Public Management benchmarks often leading to new forms of bureaucracy. In a context where the position of public officials has been weakened, ‘management’ seems to have been adopted as a source of professional legitimization. By adopting this very useful managerial posture, these civil servants find comfort in perpetuating the myth of convergence. Points for practitioners This article presents the results of a comprehensive study into the viewpoints and management practices of the roughly 500 senior civil servants in charge of local welfare policies in the French departments. How do they relate to the managerial vocabulary and management tools, given that their sector is characterized by contradictory reactions to economic and managerial rationales? The renewal of public management to which they contribute cannot be equated to an importation of methods that have shown their worth in the private sector: it seems above all to meet the new requirements on which their professional legitimacy must be built today.
Institutional impact assessment in multi-level systems: conceptualizing decentralization effects from a comparative perspective
Authors: Kuhlmann Sabine , Wayenberg Ellen 
Published: September 2015

Comparative literature on institutional reforms in multi-level systems proceeds from a global trend towards the decentralization of state functions. However, there is only scarce knowledge about the impact that decentralization has had, in particular, upon the sub-central governments involved. How does it affect regional and local governments? Do these reforms also have unintended outcomes on the sub-central level and how can this be explained? This article aims to develop a conceptual framework to assess the impacts of decentralization on the sub-central level from a comparative and policy-oriented perspective. This framework is intended to outline the major patterns and models of decentralization and the theoretical assumptions regarding de-/re-centralization impacts, as well as pertinent cross-country approaches meant to evaluate and compare institutional reforms. It will also serve as an analytical guideline and a structural basis for all the country-related articles in this Special Issue. Points for practitioners Decentralization reforms are approved as having a key role to play in the attainment of ‘good governance’. Yet, there is also the enticement on the part of state governments to offload an ever-increasing amount of responsibilities to, and overtask, local levels of government, which can lead to increasing performance disparities within local sub-state jurisdictions. Against this background, the article provides a conceptual framework to assess reform impacts from a comparative perspective. The analytical framework can be used by practitioners to support their decisions about new decentralization strategies or necessary adjustments regarding ongoing reform measures.
Cisplatin‐Induced Ototoxicity and the Effects of Intratympanic Diltiazem in a Mouse Model
Authors: Naples James G. , Parham Kourosh 
Published: September 2015

ObjectiveTo evaluate whether the calcium‐channel blocker diltiazem has protective effects against cisplatin‐induced ototoxicity in a mouse model.Study DesignOriginal basic science in vivo investigation.SettingAcademic setting: Otolaryngology–Head and Neck Surgery laboratory at University of Connecticut Health Center.SubjectsThirty‐nine female CBA/J mice.MethodsPure tone– or click‐evoked auditory brainstem responses (ABRs) were recorded in CBA/J mice to determine auditory thresholds. All mice had baseline ABRs recorded. They were then given a single cisplatin bolus (14 mg/kg), followed by 5 consecutive days of intratympanic diltiazem or saline control. Follow‐up thresholds were recorded on days 7, 14, and 21 postcisplatin. Tone‐evoked ABRs evaluated the otoprotective effect of 2‐mg/kg diltiazem in 9 mice, and dose effect was examined in response to click‐evoked ABR with 2‐ or 4‐mg/kg diltiazem in 2 groups of 15 mice.ResultsSaline‐treated ears had significantly elevated tone‐evoked auditory thresholds when compared with diltiazem‐treated ears (P =. 038) on day 7 postcisplatin only. Click‐evoked ABR thresholds were significantly elevated in saline‐treated ears versus diltiazem‐treated ears for the 2‐mg/kg group (P =. 001) and 4‐mg/kg group (P =. 011) on days 7, 14, and 21 postcisplatin.ConclusionIntratympanic diltiazem has significant protective effects against cisplatin ototoxicity at 2 and 4 mg/kg. This is the first in vivo study to demonstrate that diltiazem offers a potentially novel therapy for cisplatin‐induced ototoxicity.
Medicolegal Aspects of Iatrogenic Dysphonia and Recurrent Laryngeal Nerve Injury
Authors: Ta Jennifer H. , Liu Yuan F. , Krishna Priya 
Published: September 2015

ObjectiveTo examine aspects of litigation involving iatrogenic dysphonia and injury to the recurrent laryngeal nerve in the adult population.Study DesignLegal database review.SettingMedicolegal judicial system.Subjects and MethodsJury verdicts and settlement reports listing voice impairment or recurrent laryngeal nerve dysfunction as a primary injury in adult patients were identified in the Westlaw Database. Reports were examined for plaintiff demographics, defendant specialty, procedure performed, rates of settlements and verdicts, monetary awards, primary plaintiff symptoms, and common allegations.ResultsA total of 123 jury verdict and settlement reports were identified. General surgeons (24%), otolaryngologists (20%), and anesthesiologists (18%) were involved in the majority of cases. The procedure causing the alleged injury was primarily thyroidectomy (34%), followed by intubation (18%) and spinal instrumentation (10%). The majority of cases (70%) were decided in favor of the defendant. Where monetary awards were recorded, settlements and jury verdicts in favor of the plaintiff ranged between $4250 and $3,000,000, with a mean of $788,713. In addition to voice disturbances, complaints of dyspnea and dysphagia were commonly listed alleged injuries. The only factors associated with plaintiff verdicts were general surgery specialty (odds ratio, 6.3; 95% confidence interval, 1.7‐23.2) and claims of loss of consortium (odds ratio, 8.5; 95% confidence interval, 1.2‐60.7).ConclusionDysphonia is a common complication in a number of procedures across multiple specialties. Although the majority of cases are decided in favor or the defendant, payments awarded can be considerable. Awareness of factors involved in these medical malpractice cases can help limit physician liability.