bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repeated attempts at tracheal intubation by a single intubator associated with decreased success rates in emergency departments: an analysis of a multicentre prospective observational study
Authors: Goto Tadahiro , Watase Hiroko , Morita Hiroshi , Nagai Hideya , Brown Calvin A , Brown David F M , Hasegawa Kohei 
Published: January 2015

ObjectiveTo determine whether the success rate of repeated attempts at tracheal intubation by a single intubator was lower than those by alternate intubators in the emergency department (ED).MethodsAn analysis of data from a multicentre prospective registry (Japanese Emergency Airway Network Registry) of 13 academic and community EDs in Japan between April 2010 and August 2012. We included all adult and paediatric patients who underwent repeated attempts at tracheal intubation in the ED. We compared the intubation success rates at the second and third attempts between attempts at intubation by a single intubator who performed the previous attempts, and the attempts by alternate intubators.ResultsWe recorded 4094 patients (capture rate, 96%); 1289 patients with repeated attempts at tracheal intubation were eligible for this study. Among these, 871 patients (68%) had a second attempt at intubation by single intubators. At the second attempt, tracheal intubation by a single intubator was associated with a decreased success rate (adjusted odds ratio or AOR, 0.50; 95% CI 0.36 to 0.71), compared with alternate intubators. At the third attempt, intubation by a single intubator was also associated with a decreased success rate (58% vs 70%; unadjusted OR, 0.58; 95% CI 0.38 to 0.89). However, after adjustment for potential confounders, the association lost statistical significance (AOR, 0.89; 95% CI 0.52 to 1.56).ConclusionsIn this large multicentre study of ED patients undergoing tracheal intubation, second attempts at intubation by a single intubator, compared with those by alternate intubators, were independently associated with a decreased success rate.
Does undetectable troponin I at presentation using a contemporary sensitive assay rule out myocardial infarction? A cohort study
Authors: Kelly Anne-Maree , Klim Sharon 
Published: January 2015

AimRecent evidence suggests that an undetectable troponin level at emergency department (ED) presentation can rule out the presence of myocardial infarction (MI) in low-risk patients. The aim of this study was to investigate whether an undetectable troponin I (TnI) level at presentation using a contemporary troponin assay can accurately rule out MI at various front-door thrombolysis in myocardial infarction (fTIMI) score cut-offs.MethodsPlanned substudy of a prospective observational cohort study of patients presenting to ED with chest pain without ECG evidence of ischaemia who underwent a ‘rule out’ acute coronary syndrome process. Clinical, investigational and outcome data were collected. A contemporary TnI assay (Siemens TnI Ultra) was used. Primary outcome of interest was diagnostic accuracy for MI of undetectable initial TnI at presentation at various fTIMI scores (sensitivity, specificity, positive predictive value and negative predictive value (NPV)).Results1076 patients were studied, of whom 156 had a final diagnosis of MI (14.5%). For patients with undetectable TnI and fTIMI scores 0, 0–1, 0–2 and 0–6, sensitivities were 98.7%, 98.1%, 97.4% and 97.4%, respectively, specificities were 22.6%, 41.7%, 53.8% and 69.9%, respectively, and NPV were 99%, 99.2%, 99.2% and 99.4%, respectively. If early presenters (<2 h of symptoms) were excluded, undetectable initial troponin had 100% sensitivity (95% CI 95.2% to 100%) and NPV (95% CI 98.8% to 100%).ConclusionsUsing a contemporary TnI assay, undetectable initial TnI has high but not perfect sensitivity and NPV, unless early presenters are excluded.Trial registration numberACTRN12612000990820.
Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway
Authors: Dhanyamraju Pavan Kumar , Holz Philipp Simon , Finkernagel Florian , Fendrich Volker , Lauth Matthias 
Published: January 2015

Abstract
Uncontrolled Hedgehog (Hh) signaling is the cause of several malignancies, including the pediatric cancer medulloblastoma, a neuroectodermal tumor affecting the cerebellum. Despite the development of potent Hh pathway antagonists, medulloblastoma drug resistance is still an unresolved issue that requires the identification of novel drug targets. Following up on our observation that histone deacetylase 6 (HDAC6) expression was increased in Hh-driven medulloblastoma, we found that this enzyme is essential for full Hh pathway activation. Intriguingly, these stimulatory effects of HDAC6 are partly integrated downstream of primary cilia, a known HDAC6-regulated structure. In addition, HDAC6 is also required for the complete repression of basal Hh target gene expression. These contrasting effects are mediated by HDAC6′s impact on Gli2 mRNA and GLI3 protein expression. As a result of this complex interaction with Hh signaling, global transcriptome analysis revealed that HDAC6 regulates only a subset of Smoothened- and Gli-driven genes, including all well-established Hh targets such as Ptch1 or Gli1. Importantly, medulloblastoma cell survival was severely compromised by HDAC6 inhibition in vitro and pharmacologic HDAC6 blockade strongly reduced tumor growth in an in vivo allograft model. In summary, our data describe an important role for HDAC6 in regulating the mammalian Hh pathway and encourage further studies focusing on HDAC6 as a novel drug target in medulloblastoma. Mol Cancer Ther; 14(3); 727–39. ©2014 AACR.
Improved Circulating Tumor Cell Detection by a Combined EpCAM and MCAM CellSearch Enrichment Approach in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy
Authors: Onstenk Wendy , Kraan Jaco , Mostert Bianca , Timmermans Mieke M. , Charehbili Ayoub , Smit Vincent T.H.B.M. , Kroep Judith R. , Nortier Johan W.R. , van de Ven Saskia , Heijns Joan B. , Kessels Lonneke W. , van Laarhoven Hanneke W.M. , Bos Monique M.E.M. , van de Velde Cornelis J.H. , Gratama Jan W. , Sieuwerts Anieta M. , Martens John W.M. , Foekens John A. , Sleijfer Stefan 
Published: January 2015

Abstract
Circulating tumor cells (CTC) are detected by the CellSearch System in 20% to 25% of patients with primary breast cancer (pBC). To improve CTC detection, we investigated melanoma cell adhesion molecule (MCAM) as enrichment marker next to epithelial cell adhesion molecule (EpCAM) and tested the clinical relevance of MCAM-positive CTCs in patients with HER2-negative stage II/III pBC starting neoadjuvant chemotherapy (NAC) in the NEOZOTAC trial. Using the CellSearch System, EpCAM-positive and MCAM-positive CTCs were separately enriched from 7.5 mL blood, at baseline and after the first NAC cycle. Circulating endothelial cells (CEC) were measured using flow cytometry. Primary objective was to improve the CTC detection rate to ≥40% combining EpCAM/MCAM. Correlations of CTC and CEC counts and pathologic complete response (pCR) were also explored. At baseline, we detected EpCAM-positive and MCAM-positive CTCs in 12 of 68 (18%) and 8 of 68 (12%) patients, respectively. After one cycle, this was 7 of 44 (16%) and 7 of 44 (16%) patients, respectively. The detection rate improved from 18% at baseline and 16% after one cycle with EpCAM to 25% (P = 0.08) and 30% (P = 0.02), respectively, with EpCAM/MCAM. No patients with MCAM-positive CTCs versus 23% of patients without MCAM-positive CTCs at baseline achieved pCR (P = 0.13). EpCAM-positive CTCs and CEC counts were not correlated to pCR. Combined EpCAM/MCAM CellSearch enrichment thus increased the CTC detection rate in stage II/III pBC. We found no associations of CTC and CEC counts with pCR to NAC. The clinical relevance of MCAM-positive CTCs deserves further study. Mol Cancer Ther; 14(3); 821–7. ©2014 AACR.
A Novel Therapeutic Strategy to Rescue the Immune Effector Function of Proteolytically Inactivated Cancer Therapeutic Antibodies
Authors: Fan Xuejun , Brezski Randall J. , Deng Hui , Dhupkar Pooja M. , Shi Yun , Gonzalez Anneliese , Zhang Songlin , Rycyzyn Michael , Strohl William R. , Jordan Robert E. , Zhang Ningyan , An Zhiqiang 
Published: January 2015

AbstractPrimary and acquired resistance to anticancer antibody immunotherapies presents significant clinical challenges. Here, we demonstrate that proteolytic inactivation of cancer-targeting antibodies is an unappreciated contributor to cancer immune evasion, and the finding presents novel opportunities for therapeutic intervention. A single peptide bond cleavage in the IgG1 hinge impairs cancer cell killing due to structural derangement of the Fc region. Hinge-cleaved trastuzumab gradually accumulated on the surfaces of HER2-expressing cancer cell lines in vitro, and was greatly accelerated when the cells were engineered to express the potent bacterial IgG-degrading proteinase (IdeS). Similar to cancer-related matrix metalloproteinases (MMP), IdeS exposes a hinge neoepitope that we have developed an antibody, mAb2095-2, to specifically target the epitope. In in vitro studies, mAb2095-2 restored the lost antibody-dependent cell-mediated cytotoxicity functionality of cell-bound single-cleaved trastuzumab (scIgG-T). In vivo, mAb2095-2 rescued the impaired Fc-dependent tumor-suppressive activity of scIgG-T in a xenograft tumor model and restored the recruitment of immune effector cells into the tumor microenvironment. More importantly, an Fc-engineered proteinase-resistant version of mAb2095-2 rescued trastuzumab antitumor efficacy in a mouse tumor model with human cancer cells secreting IdeS, whereas trastuzumab alone showed significantly reduced antitumor activity in the same model. Consistently, an Fc-engineered proteinase-resistant version of trastuzumab also greatly improved antitumor efficacy in the xenograft tumor model. Taken together, these findings point to a novel cancer therapeutic strategy to rescue proteolytic damage of antibody effector function by an Fc-engineered mAb against the hinge neoepitope and to overcome cancer evasion of antibody immunity. Mol Cancer Ther; 14(3); 681–91. ©2014 AACR.
Inhibition of Stat5a/b Enhances Proteasomal Degradation of Androgen Receptor Liganded by Antiandrogens in Prostate Cancer
Authors: Hoang David T. , Gu Lei , Liao Zhiyong , Shen Feng , Talati Pooja G. , Koptyra Mateusz , Tan Shyh-Han , Ellsworth Elyse , Gupta Shilpa , Montie Heather , Dagvadorj Ayush , Savolainen Saija , Leiby Benjamin , Mirtti Tuomas , Merry Diane E. , Nevalainen Marja T. 
Published: January 2015

Abstract
Although poorly understood, androgen receptor (AR) signaling is sustained despite treatment of prostate cancer with antiandrogens and potentially underlies development of incurable castrate-resistant prostate cancer. However, therapies targeting the AR signaling axis eventually fail when prostate cancer progresses to the castrate-resistant stage. Stat5a/b, a candidate therapeutic target protein in prostate cancer, synergizes with AR to reciprocally enhance the signaling of both proteins. In this work, we demonstrate that Stat5a/b sequesters antiandrogen-liganded (MDV3100, bicalutamide, flutamide) AR in prostate cancer cells and protects it against proteasomal degradation in prostate cancer. Active Stat5a/b increased nuclear levels of both unliganded and antiandrogen-liganded AR, as demonstrated in prostate cancer cell lines, xenograft tumors, and clinical patient-derived prostate cancer samples. Physical interaction between Stat5a/b and AR in prostate cancer cells was mediated by the DNA-binding domain of Stat5a/b and the N-terminal domain of AR. Moreover, active Stat5a/b increased AR occupancy of the prostate-specific antigen promoter and AR-regulated gene expression in prostate cancer cells. Mechanistically, both Stat5a/b genetic knockdown and antiandrogen treatment induced proteasomal degradation of AR in prostate cancer cells, with combined inhibition of Stat5a/b and AR leading to maximal loss of AR protein and prostate cancer cell viability. Our results indicate that therapeutic targeting of AR in prostate cancer using antiandrogens may be substantially improved by targeting of Stat5a/b. Mol Cancer Ther; 14(3); 713–26. ©2014 AACR.
Variants for HDL-C, LDL-C, and Triglycerides Identified from Admixture Mapping and Fine-Mapping Analysis in African American Families
Authors: Shetty Priya B. , Tang Hua , Feng Tao , Tayo Bamidele , Morrison Alanna C. , Kardia Sharon L.R. , Hanis Craig L. , Arnett Donna K. , Hunt Steven C. , Boerwinkle Eric ,   the Candidate Gene Association Resource (CARe) Consortium, Rao Dabeeru C. , Cooper Richard S. , Risch Neil , Zhu Xiaofeng 
Published: January 2015

Background—
Admixture mapping of lipids was followed-up by family-based association analysis to identify variants for cardiovascular disease in African Americans.

Methods and Results—

The present study conducted admixture mapping analysis for total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. The analysis was performed in 1905 unrelated African American subjects from the National Heart, Lung and Blood Institute’s Family Blood Pressure Program (FBPP). Regions showing admixture evidence were followed-up with family-based association analysis in 3556 African American subjects from the FBPP. The admixture mapping and family-based association analyses were adjusted for age, age
2
, sex, body mass index, and genome-wide mean ancestry to minimize the confounding caused by population stratification. Regions that were suggestive of local ancestry association evidence were found on chromosomes 7 (low-density lipoprotein cholesterol), 8 (high-density lipoprotein cholesterol), 14 (triglycerides), and 19 (total cholesterol and triglycerides). In the fine-mapping analysis, 52 939 single-nucleotide polymorphisms (SNPs) were tested and 11 SNPs (8 independent SNPs) showed nominal significant association with high-density lipoprotein cholesterol (2 SNPs), low-density lipoprotein cholesterol (4 SNPs), and triglycerides (5 SNPs). The family data were used in the fine-mapping to identify SNPs that showed novel associations with lipids and regions, including genes with known associations for cardiovascular disease.

Conclusions—
This study identified regions on chromosomes 7, 8, 14, and 19 and 11 SNPs from the fine-mapping analysis that were associated with high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides for further studies of cardiovascular disease in African Americans.
Transfemoral Access Assessment for Transcatheter Aortic Valve Replacement
Authors: Okuyama Kazuaki , Jilaihawi Hasan , Kashif Mohammad , Takahashi Nobuyuki , Chakravarty Tarun , Pokhrel Heera , Patel Jigar , Forrester James S. , Nakamura Mamoo , Cheng Wen , Makkar Raj R. 
Published: January 2015

Background—
Although computed tomography (CT) is commonly used for iliofemoral evaluation for transfemoral transcatheter aortic valve replacement, many centers worldwide use invasive angiography alone for this purpose. No study to date has evaluated the value of CT over angiography for the prediction of vascular complications. In addition, no data exist for the value of noncontrast CT.

Methods and Results—

Of the 588 transcatheter aortic valve replacement patients, we reviewed 496 consecutive transfemoral cases. Vessel diameters were measured by CT or angiography. Sheath-related complication (SRC) was defined as an iliofemoral arterial injury not including a cannulation site. Receiver operating characteristic models were generated using sheath-to-iliofemoral artery ratios as a variable and SRC as an end point. In patients undergoing both contrast CT and angiography (n=283; 35 SRCs), contrast CT showed a greater predictive value than angiography by area under the curve
P
<0.001): 0.87 (95% confidence interval: 0.82–0.91) versus 0.72 (95% confidence interval: 0.66–0.77). In patients undergoing both noncontrast CT and angiography (n=103; 17 SRCs), there was no difference between noncontrast CT and angiography: 0.79 (95% confidence interval: 0.70–0.86) versus 0.73 (95% confidence interval: 0.63–0.81). Three-dimensional assessments of calcification and tortuosity provided limited additional value for SRC prediction.

Conclusions—
Contrast CT has a greater predictive value for post-transcatheter aortic valve replacement vascular complications than angiography. Because these complications increase mortality, an accurate assessment of the vasculature is a critical component of proper access selection.
Obese Subjects Show Sex-Specific Differences in Right Ventricular Hypertrophy
Authors: Rider Oliver J. , Lewis Andrew J.M. , Lewandowski Adam J. , Ntusi Ntobeko , Nethononda Richard , Petersen Steffen E. , Francis Jane M. , Pitcher Alex , Banerjee Rajarshi , Leeson Paul , Neubauer Stefan 
Published: January 2015

Background—
As right ventricular (RV) remodeling in obesity remains underinvestigated, and the impact of left ventricular (LV) diastolic dysfunction on RV hypertrophy is unknown, we aimed to investigate whether (1) sex-specific patterns of RV remodeling exist in obesity and (2) LV diastolic dysfunction in obesity is related to RV hypertrophy.

Methods and Results—

Seven hundred thirty-nine subjects (women, n=345; men, n=394) without identifiable cardiovascular risk factors (body mass index [BMI], 15.3–59.2 kg/m
2
) underwent cardiovascular magnetic resonance (1.5 T) to measure RV mass (g), RV end-diastolic volume (mL), RV mass/volume ratio, and LV diastolic peak filling rate (mL/s). All subjects were normotensive (average, 119±11/73±8 mm Hg), normoglycaemic (4.8±0.5 mmol/L), and normocholesterolaemic (4.8±0.9 mmol/L) at the time of scanning. Across both sexes, there was a moderately strong positive correlation between BMI and RV mass (men, +0.8 g per BMI point increase; women, +1.0 g per BMI point increase; both
P
<0.001). Whereas women exhibited RV cavity dilatation (RV end-diastolic volume, +1.0 mL per BMI point increase;
P
<0.001), BMI was not correlated with RV end-diastolic volume in men (
R
=0.04;
P
=0.51). Concentric RV remodeling was present in both sexes, with RV mass/volume ratio being positively correlated to BMI (men,
R
=0.41; women,
R
=0.51; both
P
<0.001). Irrespective of sex, the LV peak filling rate was negatively correlated with both RV mass (men,
R
=−0.43; women,
R
=−0.44; both
P
<0.001) and RV mass/volume ratio (men,
R
=−0.37; women,
R
=−0.35; both
P
<0.001).

Conclusions—
A sex difference in RV remodeling exists in obesity. Whereas men exhibit concentric RV remodeling, women exhibit a mixed pattern of eccentric and concentric remodeling. Regardless of sex, reduced LV diastolic function is associated with concentric RV remodeling.
Long-Term Results of Transapical Versus Transfemoral TAVI in a Real World Population of 1000 Patients With Severe Symptomatic Aortic Stenosis
Authors: Schymik Gerhard , Würth Alexander , Bramlage Peter , Herbinger Tanja , Heimeshoff Martin , Pilz Lothar , Schymik Jan S. , Wondraschek Rainer , Süselbeck Tim , Gerhardus Jan , Luik Armin , Gonska Bernd-Dieter , Posival Herbert , Schmitt Claus , Schröfel Holger 
Published: January 2015

Background—
Transapical transcatheter aortic valve implantation is generally perceived to be associated with increased morbidity compared with transfemoral transcatheter aortic valve implantation. We aimed to compare access-related complications and survival using propensity score matching.

Methods and Results—

Prospective, single-center registry of 1000 consecutive patients undergoing transapical and transfemoral transcatheter aortic valve implantation between May 2008 and April 2012. Transapical was performed in 413 patients and transfemoral in 587 patients. Patients with transapical access were less often women and less had pulmonary hypertension. Further they had more peripheral arterial disease, coronary artery disease, carotid stenosis, and recurrent surgery and a higher logistic EuroSCORE I (24.3%±16.2% for transapical versus 22.2%±16.2% for transfemoral;
P
<0.01). After building 2 propensity score–matched groups of 354 patients each with either access route (total 708 patients), baseline characteristics were comparable. In this analysis, there was no significant difference in 30 day mortality (5.9% transapical versus 8.5% transfemoral;
P
=0.19), the rate of myocardial infarction (2.5% transapical versus 2.0% transfemoral;
P
=0.61), stroke (2.0% transapical versus 2.3% transfemoral;
P
=0.79), bleeding complications, pacemaker implantation rates, or moderate aortic insufficiency. Stage 1 renal complications were more common in transapical patients (odds ratio, 2.81; 95% confidence interval, 1.93–4.09), whereas major vascular complications were less common (odds ratio, 0.14; 95% confidence interval, 0.06–0.29). Survival probability over the long term was not statistically different (hazard ratio, 0.89; 95% confidence interval, 0.72–1.10; log-rank Test,
P
=0.27).

Conclusions—
The data demonstrate that in an experienced multidisciplinary heart team, either access route can be performed with comparable results.
Morphine Is Associated With a Delayed Activity of Oral Antiplatelet Agents in Patients With ST-Elevation Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Authors: Parodi Guido , Bellandi Benedetta , Xanthopoulou Ioanna , Capranzano Piera , Capodanno Davide , Valenti Renato , Stavrou Katerina , Migliorini Angela , Antoniucci David , Tamburino Corrado , Alexopoulos Dimitrios 
Published: January 2015

Background—
Morphine is recommended in patients with ST-segment–elevation myocardial infarction, including those undergoing primary percutaneous coronary intervention. Suboptimal antiplatelet effect during and after primary percutaneous coronary intervention is associated with increased thrombotic complications. It was hypothesized a potential drug–drug interaction between morphine and antiplatelet agents. We sought to assess platelet inhibition after a loading dose of the currently recommended antiplatelet agents in ST-segment–elevation myocardial infarction patients according to morphine use.

Methods and Results—

Three hundred patients undergoing primary percutaneous coronary intervention receiving either prasugrel (n=95) or ticagrelor (n=205) loading dose had platelet reactivity assessed by VerifyNow 1, 2, and 4 hours after loading dose. Patients treated with morphine (n=95; 32%) had a higher incidence of vomit (15% versus 2%;
P
=0.001). P2Y
12
reactivity units 2 hours after the loading dose was 187 (153–221) and 133 (102–165) in patient with and without morphine (
P
<0.001); the difference persisted after excluding patients with vomit (
P
<0.0001). High residual platelet reactivity (P2Y
12
reactivity units ≥208) at 2 hours was found in 53% and 29% patients with and without morphine (
P
<0.001) and without difference between prasugrel and ticagrelor patients. The independent predictors of high residual platelet reactivity at 2 hours were morphine use (odds ratio, 2.91 [1.71–4.97];
P
<0.0001) and age (odds ratio, 1.03 [1.01–1.05];
P
=0.010). Morphine remained associated with high residual platelet reactivity after propensity score adjustment (c-statistic, 0.68; 95% confidence interval, 0.66–0.70;
P
=0.879 for Hosmer–Lemeshow test).

Conclusions—
In patients with ST-segment–elevation myocardial infarction, morphine use is associated with a delayed onset of action of the oral antiplatelet agents. This association persisted after adjusting for the propensity to receive morphine and after excluding patients with vomit.