bluuebunny/crossref_metadata_2025 huggingface dataset:
An Efficient One Pot Protocol to the Annulation of Face “d” of Benzazepinone Ring with Pyrazole, Isoxazole, and Pyrimidine Nucleus through the Corresponding Oxoketene Dithioacetal Derivative
Authors: Anand Aditi , Kaur Navjeet , Kishore Dharma
Published: August 2014

A highly facile single step approach to the annulation of face “d” of benzazepinone nucleus with pyrazole, isoxazole, and pyrimidine ring has been described. The annulation proceeded smoothly on the reaction of oxoketene dithioacetal derivative 3 with (i) NH2–NH2·H2O, (ii) NH2OH·HCl, (iii) acetamidine hydrochloride, (iv) guanidine nitrate, (v) urea, and (vi) thiourea which yielded the pyrazolo, isoxazolo, and pyrimido annulated analogues of benzazepinone 4–9, respectively, in acceptable yields. The 4-ketene dithioacetal analogue of 7-fluorobenzo[b]azepine-2,5-dione (3) was in turn obtained from the reaction of 7-fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (2) (with CS2 + CH3I in presence of t-BuOK). 7-Fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (2) resulted from the acylation of p-fluoroaniline with succinyl chloride followed by cyclocondensation of the later with polyphosphoric acid (PPA).
Impaired Object Handling during Bimanual Task Performance in Multiple Sclerosis
Authors: Gorniak Stacey L. , Plow Matthew , McDaniel Corey , Alberts Jay L.
Published: August 2014

We investigated the kinetic features of manual dexterity and fine motor control during a task that resembles an activity of daily living in 30 persons with relapsing-remitting multiple sclerosis (PwMS). Specifically, a novel two-transducer system was used to measure time and grip-load forces during a bimanual task that is similar to opening and closing a jar. We hypothesized that PwMS would have increased grip force production, deteriorations in kinetic timing, and preserved grip-load coupling indices compared to healthy controls (i.e., young and older adults). Increased grip force production and deterioration in timing indices were confirmed in PwMS. Abnormal grip-load coupling was exhibited by PwMS, in contrast to healthy participants. The correlation between task time and self-reported disability scores suggests that objective measurement of impaired upper-extremity movements relates to perception of overall function.
Gap Minimization for Peer-Evaluation in DEA Cross-Efficiency
Authors: Yang Anrong , Zhang Zigang , Zhang Yishi , Chen Dunliang
Published: August 2014

Cross-efficiency evaluation is an effective and widely used method for ranking decision making units (DMUs) in data envelopment analysis (DEA). Gap minimization criterion is introduced in aggressive and benevolent cross-efficiency methods to avoid possible extreme efficiency from peer-evaluation and to get equitable results. On the basis of this criterion, a weighted cross-efficiency method with similarity distance that, respectively, considers the aggressive and the benevolent formulations is proposed to determine cross-efficiency. The weights of the cross-evaluation determined by this method are positively influenced by self-evaluation and thus are propitious to resolving conflict. Numerical demonstration reveals the feasibility of the proposed method.
Cyanoacrylate Skin Surface Stripping and the 3S-Biokit Advent in Tropical Dermatology: A Look from Liège
Authors: Piérard Gérald E. , Piérard-Franchimont Claudine , Paquet Philippe , Hermanns-Lê Trinh , Radermacher Jean , Delvenne Philippe
Published: August 2014

In the dermatopathology field, some simple available laboratory tests require minimum equipment for establishing a diagnosis. Among them, the cyanoacrylate skin surface stripping (CSSS), formerly named skin surface biopsy or follicular biopsy, represents a convenient low cost procedure. It is a minimally invasive method collecting a continuous sheet of stratum corneum and horny follicular casts. In the vast majority of cases, it is painless and is unassociated with adverse events. CSSS can be performed in subjects of any age. The method has a number of applications in diagnostic dermatopathology and cosmetology, as well as in experimental dermatology settings. A series of derived analytic procedures include xerosis grading, comedometry, corneofungimetry, corneodynamics of stratum corneum renewal, corneomelametry, corneosurfametry, and corneoxenometry.
Transfusion Strategy: Impact of Haemodynamics and the Challenge of Haemodilution
Authors: Jakobsen Carl-Johan
Published: August 2014

Blood transfusion is associated with increased morbidity and mortality and numerous reports have emphasised the need for reduction. Following this there is increased attention to the concept of patient blood management. However, bleeding is relatively common following cardiac surgery and is further enhanced by the continued antiplatelet therapy policy. Another important issue is that cardiopulmonary bypass leads to haemodilution and a potential blood loss. The basic role of blood is oxygen transport to the organs. The determining factors of oxygen delivery are cardiac output, haemoglobin, and saturation. If oxygen delivery/consumption is out of balance, the compensation mechanisms are simple, as a decrease in one factor results in an increase in one or two other factors. Patients with coexisting cardiac diseases may be of particular risk, but studies indicate that patients with coexisting cardiac diseases tolerate moderate anaemia and may even benefit from a restrictive transfusion regimen. Further it has been shown that patients with reduced left ventricular function are able to compensate with increased cardiac output in response to bleeding and haemodilution if normovolaemia is maintained. In conclusion the evidence supports that each institution establishes its own patient blood management strategy to both conserve blood products and maximise outcome.
Spatiotemporal Access Model Based on Reputation for the Sensing Layer of the IoT
Authors: Guo Yunchuan , Yin Lihua , Li Chao , Qian Junyan
Published: August 2014

Access control is a key technology in providing security in the Internet of Things (IoT). The mainstream security approach proposed for the sensing layer of the IoT concentrates only on authentication while ignoring the more general models. Unreliable communications and resource constraints make the traditional access control techniques barely meet the requirements of the sensing layer of the IoT. In this paper, we propose a model that combines space and time with reputation to control access to the information within the sensing layer of the IoT. This model is called spatiotemporal access control based on reputation (STRAC). STRAC uses a lattice-based approach to decrease the size of policy bases. To solve the problem caused by unreliable communications, we propose both nondeterministic authorizations and stochastic authorizations. To more precisely manage the reputation of nodes, we propose two new mechanisms to update the reputation of nodes. These new approaches are the authority-based update mechanism (AUM) and the election-based update mechanism (EUM). We show how the model checker UPPAAL can be used to analyze the spatiotemporal access control model of an application. Finally, we also implement a prototype system to demonstrate the efficiency of our model.
Some Eocene Cerithioids (Gastropoda, Mollusca) from Kutch, Western India, and Their Bearing on Palaeobiogeography of the Indian Subcontinent
Authors: Halder Kalyan , Sinha Piyali
Published: August 2014

The cerithioids are a diverse group of gastropods found globally as fossil and living animals during the Cenozoic Era. Their systematics is riddled with problems stemming from large morphological variability, homoplasy, and wide geographical distribution. Six cerithioid species are described here from the lower Middle Eocene of Kutch, Gujarat, western India. All but two are new species. They are Palmerella kutchensis, Tenagodus? sowerbyi, Potamides archiaci, and Cerithium harudiensis. The rest are new records from Kutch and were known only from Pakistan. A palaeobiogeographical review based on major published records of benthic molluscs from Pakistan reveals strong endemism. The cerithioid faunas from different parts of Pakistan and this report from Kutch also show strong endemism and often quite localized development. It is argued here that unhindered faunal mixing was not possible in this province since these newly evolved basins were restricted in nature in their Lower Cenozoic history.
On Analog of Fourier Transform in Interior of the Light Cone
Authors: Shtepina Tatyana
Published: August 2014

We introduce an analog of Fourier transformFhρin interior of light cone that commutes with the action of the Lorentz group. We describe some properties ofFhρ, namely, its action on pseudoradial functions and functions being products of pseudoradial function and space hyperbolic harmonics. We prove thatFhρ-transform gives a one-to-one correspondence on each of the irreducible components of quasiregular representation. We calculate the inverse transform too.
Bifurcation Analysis and Sliding Mode Control of Chaotic Vibrations in an Autonomous System
Authors: Du Wenju , Chu Yandong , Zhang Jiangang , Chang Yingxiang , Yu Jianning , An Xinlei
Published: August 2014

We study the bifurcations and sliding mode control of chaotic vibrations in an autonomous system. More precisely, a Hopf bifurcation controller is designed so as to control the unstable subcritical Hopf bifurcation to the stable supercritical Hopf bifurcation. Research result shows that the control method can work very well in Hopf bifurcation control. Besides, we controlled the system to any fixed point and any periodic orbit to eliminate the chaotic vibration by means of sliding mode method. And the numerical simulations were presented to confirm the effectiveness of the controller.
Endothelial Nitric Oxide Synthase Gene Polymorphisms and the Risk of Hypertension in an Indian Population
Authors: Shankarishan Priyanka , Borah Prasanta Kumar , Ahmed Giasuddin , Mahanta Jagadish
Published: August 2014

Genetic variants of eNOS gene play a significant role in the pathogenesis of hypertension. Many environmental factors have, also, been implicated in the aetiology of hypertension. We carried out an age-matched case-control study among adults. Hypertension was defined according to JNC-VII criteria and eNOS gene polymorphisms were determined by PCR and PCR followed by PCR-RFLP. eNOS intron 4 aa genotype (adjusted OR 6.81; 95% CI 2.29–20.25) and eNOS 894TT genotype (adjusted OR 7.84; 95% CI 2.57–23.96) were associated with the risk of hypertension. Tobacco users (either smoking/chewing or both) with eNOS intron 4 aa genotype (OR 14.00: 95% CI 1.20–163.37), eNOS 894GG genotype (OR 5.56: 95% CI 3.72–8.31), and eNOS T-786C CC genotype (OR 9.00: 95% CI 1.14–71.04) were at an increased risk of hypertension. Similarly a significant gene-environment interaction was observed between individuals consuming alcohol with eNOS intron 4 aa genotype (OR 12.00: 95% CI 1.20–143.73) and eNOS 894GG genotype (OR 1.95: 95% CI 1.35–2.81). The present study identified few susceptible genotypes of the eNOS gene with the risk of hypertension. Moreover, the interactive effects between the environmental factors and the risk of hypertension were dependent on the eNOS genotypes.
A Variable Neighborhood Walksat-Based Algorithm for MAX-SAT Problems
Authors: Bouhmala Noureddine
Published: August 2014

The simplicity of the maximum satisfiability problem (MAX-SAT) combined with its applicability in many areas of artificial intelligence and computing science made it one of the fundamental optimization problems. This NP-complete problem refers to the task of finding a variable assignment that satisfies the maximum number of clauses (or the sum of weights of satisfied clauses) in a Boolean formula. The Walksat algorithm is considered to be the main skeleton underlying almost all local search algorithms for MAX-SAT. Most local search algorithms including Walksat rely on the 1-flip neighborhood structure. This paper introduces a variable neighborhood walksat-based algorithm. The neighborhood structure can be combined easily using any local search algorithm. Its effectiveness is compared with existing algorithms using 1-flip neighborhood structure and solvers such as CCLS and Optimax from the eighth MAX-SAT evaluation.
Determinants of Mortality among Adult HIV-Infected Patients on Antiretroviral Therapy in a Rural Hospital in Southeastern Nigeria: A 5-Year Cohort Study
Authors: Eguzo Kelechi N. , Lawal Adegboyega K. , Eseigbe Cynthia E. , Umezurike Chisara C.
Published: August 2014

Background. Study examined the determinants of mortality among adult HIV patients in a rural, tertiary hospital in southeastern Nigeria, comparing mortality among various ART regimens.Methods. Retrospective cohort study of 1069 patients on ART between August 2008 and October 2013. Baseline CD4 counts, age, gender, and ART regimen were considered in this study. Kaplan-Meier method was used to estimate survival and Cox proportional hazards models to identify multivariate predictors of mortality. Median follow-up period was 24 months (IQR 6–45).Results. 78 (7.3%) patients died with 15.6% lost to followup. Significant independent predictors of mortality include age (>45), sex (male > female), baseline CD4 stage (<200), and ART combination. Adjusted mortality hazard was 3 times higher among patients with CD4 count <200 cells/μL than those with counts >500 (95% CI 1.69–13.59). Patients on Truvada-based first-line regimens were 88% more likely to die than those on Combivir-based first line (95% CI 1.05–3.36), especially those with CD4 count <200 cells/μL.Conclusion. Study showed lower mortality than most studies in Nigeria and Africa, with mortality higher among males and patients with CD4 count <200. Further studies are recommended to further compare treatment outcomes between Combivir- and Truvada-based regimens in resource-limited settings using clinical indicators.
Milk and Blood Pharmacokinetics of Tylosin and Tilmicosin following Parenteral Administrations to Cows
Authors: Avci Tulay , Elmas Muammer
Published: August 2014

The aim of this study is to determine the pharmacokinetics of tylosin and tilmicosin in serum and milk in healthy Holstein breed cows (n=12) and reevaluate the amount of residue in milk. Following the intramuscular administration of tylosin, the maximum concentrations (Cmax) in serum and milk were found to be1.30±0.24and4.55±0.23 µg/mL, the time required to reach the peak concentration (tmax) was found to be 2nd and 4th h, and elimination half-lives (t1/2β) were found to be20.46±2.08and26.36±5.55 h, respectively. Following the subcutaneous administration of tilmicosin, theCmaxin serum and milk were found to be0.86±0.20and20.16±1.13 µg/mL, thetmaxwas found to be 1st and 8th h, and thet1/2βwere found to be29.94±6.65and43.02±5.18 h, respectively.AUCmilk/AUCserumandCmax-milk/Cmax-serumrates, which are indicators for determining the rate of drugs that pass into milk, were, respectively, calculated as5.01±0.72and3.61±0.69for tylosin and23.91±6.38and20.16±1.13for tilmicosin. In conclusion, it may be stated that milk concentration of tylosin after parenteral administration is higher than expected like tilmicosin and needs more withdrawal period for milk than reported.
Tuberculosis of the Adrenal Gland: A Case Report and Review of the Literature of Infections of the Adrenal Gland
Authors: Upadhyay Jagriti , Sudhindra Praveen , Abraham George , Trivedi Nitin
Published: August 2014

Infections of the adrenal glands remain an important cause of adrenal insufficiency, especially in the developing world. Indeed, when Thomas Addison first described the condition that now bears his name over 150 years ago, the vast majority of cases were attributable to tuberculosis. Here we describe a classic, but relatively uncommon, presentation in the United States of adrenal insufficiency followed by a review of the current literature pertaining to adrenal infections.
The Finite Element Numerical Modelling of 3D Magnetotelluric
Authors: Cao Ligang , Liu Yun
Published: August 2014

The ideal numerical simulation of 3D magnetotelluric was restricted by the methodology complexity and the time‐consuming calculation. Boundary values, the variation of weighted residual equation, and the hexahedral mesh generation method of finite element are three major causes. A finite element method for 3D magnetotelluric numerical modeling is presented in this paper as a solution for the problem mentioned above. In this algorithm, a hexahedral element coefficient matrix for magnetoelluric finite method is developed, which solves large‐scale equations using preconditioned conjugate gradient of the first‐type boundary conditions. This algorithm is verified using the homogeneous model, and the positive landform model, as well as the low resistance anomaly model.
Risk Factors and Surgical Refinements of Postresective Mandibular Reconstruction: A Retrospective Study
Authors: Sakakibara Akiko , Hashikawa Kazunobu , Yokoo Satoshi , Sakakibara Shunsuke , Komori Takahide , Tahara Shinya
Published: August 2014

Background. Postresective mandibular reconstruction is common in cases of oral and mandibular tumors. However, complications such as infection, plate exposure, or plate fracture can occur. We identified several significant risk factors of complications after reconstructive surgery and compared the effectiveness of different surgical techniques for reducing the incidence of complications. Methods. This study is a retrospective analysis of 28 oromandibular cancer cases that required reconstructive surgery between January 1999 and December 2011 at Kobe University Graduate School of Medicine in Japan. All cases were classified using Hashikawa’s CAT and Eichner’s classification methods. Then, we determined whether these classifications and different treatment or surgical methods were significantly related to complications. Results. Complications after mandibular reconstruction occurred in 10/28 patients (36%). Specifically, five patients had plate fractures, four had plate exposures, and one had an infection. Radiation therapy and closure without any flaps were significantly related to infection or plate exposure. The wrap-around technique of securing reconstruction plates was used in 14 cases, whereas the run-through technique was used in two cases. Conclusions. The success of mandibular reconstruction depends on both mechanical and biological factors, such as the location of defects, presence of occlusions, and the amount of vascularization of the flap.
Nontrivial Solutions of a Fully Fourth-Order Periodic Boundary Value Problem
Authors: Li Haitong , Pei Minghe , Wang Libo
Published: August 2014

We investigate the solvability of a fully fourth-order periodic boundary value problem of the formx(4)=f(t,x,x′,x′′,x′′′),  x(i)(0)=x(i)(T),      i=0,1,2,3,wheref:[0,T]×R4→Rsatisfies Carathéodory conditions. By using the coincidence degree theory, the existence of nontrivial solutions is obtained. Meanwhile, as applications, some examples are given to illustrate our results.
Early Detection of Atrophy of Foot Muscles in Chinese Patients of Type 2 Diabetes Mellitus by High-Frequency Ultrasonography
Authors: Wang Xiaohui , Chen Liang , Liu Weiwei , Su Benli , Zhang Yuhong
Published: August 2014

The aim of this study was to evaluate the diagnostic value of high-frequency ultrasonography in detecting atrophy of foot muscles in Chinese patients of type 2 diabetes mellitus (T2DM). Chinese patients of T2DM with (n=56) or without (n=50) diabetic peripheral neuropathy (DPN) and the control subjects (n=50) were enrolled. The nondominant foot of all subjects was examined with high-frequency ultrasonography. The transverse diameter, thickness, and cross-sectional area of the extensor digitorum brevis muscle (EDB) and the thickness of the muscles of the first interstitium (MILs) were measured. The results showed that the ultrasonographic transverse diameter, thickness, and cross-sectional area of EDB and the thickness of MILs in patients of T2DM with DPN were significantly smaller than those in patients of T2DM without DPN (allP<0.01) and those in the control subjects (allP<0.01). The transverse diameter and cross-sectional area of the EDB and thickness of MILs in patients of T2DM without DPN were significantly smaller than those of the control subjects (allP<0.01). In conclusion, the atrophy of foot muscle in Chinese T2DM patients can be detected by high-frequency ultrasonography. Notably, ultrasonography may detect early atrophy of foot muscles in patients without DPN.
Wavelet Analysis Increases Sensitivity and Specificity of Spirography for Ambulatory Tremor Discrimination
Authors: Kragelj Veronika , Georgiev Dejan , Pirtošek Zvezdan , Ribarič Samo
Published: August 2014

The most frequently seen types of tremor are essential (ET) and parkinsonian tremor (PT) and in some patients clinical characteristics of these tremor types overlap. It is vital to distinguish between these two types of tremor in order to reach the right diagnosis and select the appropriate treatment. One of the widely used methods for tremor detection and discrimination, appropriate for a quick ambulatory assessment of the patient’s tremor, is spirography. With spirography, the tremor can be observed through several parameters, for example, tremor spectrum and spiral image, which give useful information for its identification. Standard spirography parameters of ET and PT can overlap; therefore, these parameters are often not enough for identification of the observed tremor. To increase the specificity and sensitivity of spirography for PT, ET and normal, tremor free controls, we used the wavelet analysis with Morlet wavelet transform. To facilitate analysis, comparison, storage, and retrieval of spirography tremor records we also developed an integrated computer assisted spirography system that increases the convenience of outpatient tremor identification and follow-up. We conclude that wavelet analysis of spirography records increases the sensitivity and specificity of the method, thus, facilitating the distinction between ET and PT.
Lung Cancer Mortality and Radon Concentration in a Chronically Exposed Neighborhood in Chihuahua, Mexico: A Geospatial Analysis
Authors: Hinojosa de la Garza Octavio R. , Sanín Luz H. , Montero Cabrera María Elena , Serrano Ramirez Korina Ivette , Martínez Meyer Enrique , Reyes Cortés Manuel
Published: August 2014

This study correlated lung cancer (LC) mortality with statistical data obtained from government public databases. In order to asses a relationship between LC deaths and radon accumulation in dwellings, indoor radon concentrations were measured with passive detectors randomly distributed in Chihuahua City. Kriging (K) and Inverse-Distance Weighting (IDW) spatial interpolations were carried out. Deaths were georeferenced and Moran’sIcorrelation coefficients were calculated. The mean values (overn=171) of the interpolation of radon concentrations of deceased’s dwellings were 247.8 and 217.1 Bq/m3, for K and IDW, respectively. Through the Moran’sIvalues obtained, correspondingly equal to 0.56 and 0.61, it was evident that LC mortality was directly associated with locations with high levels of radon, considering a stable population for more than 25 years, suggesting spatial clustering of LC deaths due to indoor radon concentrations.
Pathophysiology of Cisplatin-Induced Acute Kidney Injury
Authors: Ozkok Abdullah , Edelstein Charles L.
Published: August 2014

Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. A known complication of cisplatin administration is acute kidney injury (AKI). The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney. There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Inhibition of the proinflammatory cytokines TNF-αor IL-33 or depletion of CD4+ T cells or mast cells protects against cisplatin-induced AKI. Cisplatin also causes endothelial cell injury. An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality.
FDA Approval Summary: Vemurafenib for Treatment of Unresectable or Metastatic Melanoma with the BRAFV600E Mutation
Authors: Kim Geoffrey , McKee Amy E. , Ning Yang-Min , Hazarika Maitreyee , Theoret Marc , Johnson John R. , Xu Qiang Casey , Tang Shenghui , Sridhara Rajeshwari , Jiang Xiaoping , He Kun , Roscoe Donna , McGuinn W. David , Helms Whitney S. , Russell Anne Marie , Miksinski Sarah Pope , Zirkelbach Jeanne Fourie , Earp Justin , Liu Qi , Ibrahim Amna , Justice Robert , Pazdur Richard
Published: August 2014

On August 17, 2011, the U.S. Food and Drug Administration (FDA) approved vemurafenib tablets (Zelboraf, Hoffmann-LaRoche Inc.) for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation as detected by an FDA-approved test. The cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Inc.) was approved concurrently. An international, multicenter, randomized, open-label trial in 675 previously untreated patients with BRAFV600E mutation–positive unresectable or metastatic melanoma allocated 337 patients to receive vemurafenib, 960 mg orally twice daily, and 338 patients to receive dacarbazine, 1,000 mg/m2 intravenously every 3 weeks. Overall survival was significantly improved in patients receiving vemurafenib [HR, 0.44; 95% confidence interval (CI), 0.33–0.59; P < 0.0001]. Progression-free survival was also significantly improved in patients receiving vemurafenib (HR, 0.26; 95% CI, 0.20–0.33; P < 0.0001). Overall response rates were 48.4% and 5.5% in the vemurafenib and dacarbazine arms, respectively. The most common adverse reactions (≥30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous cell carcinomas or keratoacanthomas were detected in approximately 24% of patients treated with vemurafenib. Other adverse reactions included hypersensitivity, Stevens–Johnson syndrome, toxic epidermal necrolysis, uveitis, QT prolongation, and liver enzyme laboratory abnormalities. Clin Cancer Res; 20(19); 4994–5000. ©2014 AACR.
Somatic ERCC2 Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma
Authors: Van Allen Eliezer M. , Mouw Kent W. , Kim Philip , Iyer Gopa , Wagle Nikhil , Al-Ahmadie Hikmat , Zhu Cong , Ostrovnaya Irina , Kryukov Gregory V. , O'Connor Kevin W. , Sfakianos John , Garcia-Grossman Ilana , Kim Jaegil , Guancial Elizabeth A. , Bambury Richard , Bahl Samira , Gupta Namrata , Farlow Deborah , Qu Angela , Signoretti Sabina , Barletta Justine A. , Reuter Victor , Boehm Jesse , Lawrence Michael , Getz Gad , Kantoff Philip , Bochner Bernard H. , Choueiri Toni K. , Bajorin Dean F. , Solit David B. , Gabriel Stacey , D'Andrea Alan , Garraway Levi A. , Rosenberg Jonathan E.
Published: August 2014

Cisplatin-based chemotherapy is the standard of care for patients with muscle-invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although molecular determinants of cisplatin response are incompletely understood. We performed whole-exome sequencing on pretreatment tumor and germline DNA from 50 patients with muscle-invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (25 pT0/pTis “responders,” 25 pT2+ “nonresponders”) to identify somatic mutations that occurred preferentially in responders. ERCC2, a nucleotide excision repair gene, was the only significantly mutated gene enriched in the cisplatin responders compared with nonresponders (q < 0.01). Expression of representative ERCC2 mutants in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared with wild-type ERCC2. The lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer, and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle-invasive urothelial carcinoma.

Significance: Somatic ERCC2 mutations correlate with complete response to cisplatin-based chemosensitivity in muscle-invasive urothelial carcinoma, and clinically identified mutations lead to cisplatin sensitivity in vitro. Nucleotide excision repair pathway defects may drive exceptional response to conventional chemotherapy. Cancer Discov; 4(10); 1140–53. ©2014 AACR.

See related commentary by Turchi et al., p. 1118

This article is highlighted in the In This Issue feature, p. 1103
The Four-Year Course of Major Depressive Disorder: The Role of Staging and Risk Factor Determination
Authors: Boschloo Lynn , Schoevers Robert A. , Beekman Aartjan T.F. , Smit Johannes H. , van Hemert Albert M. , Penninx Brenda W.J.H.
Published: August 2014

Background: Much is still unclear about the mechanisms underlying the course of major depressive disorder (MDD). This study aimed to identify risk factors that predict a poor prognosis of MDD while taking into consideration its chronicity at baseline. Methods: In patients with MDD (n = 767), we examined whether baseline clinical factors, sociodemographics, childhood trauma, personality and life events predicted the 4-year course (i.e. sustained recovery, temporary recovery and chronic course) of MDD. Baseline chronicity of MDD was taken into account by testing whether associations were different for patients with nonchronic versus chronic MDD at baseline. Results: In patients with nonchronic MDD at baseline, 27.8% developed a chronic disorder during follow-up, whereas 53.0% of patients with chronic MDD at baseline had a persistent chronic disorder during follow-up. Severity of MDD, childhood trauma and greater age were important general risk factors for a poor prognosis, independent of MDD chronicity at baseline. In contrast, low extraversion was only important for the course of nonchronic MDD at baseline, while higher education and negative life events (in patients with high neuroticism) were only relevant for the course of chronic MDD at baseline. Conclusions: One out of 4 patients with nonchronic MDD progressed to a chronic disorder, while half of the patients with chronic MDD remained chronic during follow-up. Since several risk factors for a poor prognosis differed for patients with nonchronic and chronic MDD at baseline, treatment targets should be adjusted for current chronicity of MDD.
Association of Glycemic Control With Mortality in Patients With Diabetes Mellitus Undergoing Percutaneous Coronary Intervention
Authors: Sharma Praneet K. , Agarwal Shikhar , Ellis Stephen G. , Goel Sachin S. , Cho Leslie , Tuzcu E. Murat , Lincoff A. Michael , Kapadia Samir R.
Published: August 2014

Background—

Diabetes mellitus adversely affects outcomes in patients undergoing percutaneous coronary intervention. The association of baseline hemoglobin A1c (HbA1c) at the time of percutaneous coronary intervention with long-term mortality is unknown.

Methods and Results—

Consecutive patients with diabetes mellitus undergoing percutaneous coronary intervention between 1998 and 2008 were identified from our institutional database. Characteristics and outcomes of patients were compared based on HbA1c categories (≤7%, 7.1%–8.0%, 8.1%–9.0%, 9.1%–10.0%, and >10.0%). Among 3008 patients, 1321 had HbA1c ≤7%, 782 with HbA1c 7.1% to 8.0%, 401 with HbA1c 8.1% to 9.0%, 229 with HbA1c 9.1% to 10.0%, and 275 with HbA1c >10%. Compared with low HbA1c (≤7%), those with highest HbA1c (>10%) were younger (56.5 versus 67.5 years), had higher total cholesterol (188 versus 157 mg/dL), more insulin use (54% versus 26%), and presented more often with ST-segment–elevation myocardial infarction (10.9% versus 5.6%). Those with lower HbA1c (≤7%) more often had other comorbidities (more hypertension [90.4% versus 82.5%] and chronic renal failure [14.4% versus 7.6%]). On multivariable Cox proportional hazards modeling, survival analysis demonstrated a trend toward higher mortality with higher HbA1c. Compared with the reference group of patients with HbA1c ≤7%, patients with HbA1c >10% had a significantly higher mortality on follow-up (hazard ratio [95% confidence interval], 1.52 [1.17–1.99];
P
=0.002). This difference was primarily seen among noninsulin users; however, insulin users had no significant differences in mortality among HbA1c categories.

Conclusions—

Patients with diabetes mellitus who were not on insulin and had poor glycemic control (HbA1c >10%) had significantly higher long-term mortality after percutaneous coronary intervention as compared with those with well-controlled diabetes mellitus, evidenced by HbA1c ≤7%. Insulin users, however, had similar rates of mortality among different HbA1c categories.
Trial Occlusion to Assess the Risk of Persistent Pulmonary Arterial Hypertension After Closure of a Large Patent Ductus Arteriosus in Adolescents and Adults With Elevated Pulmonary Artery Pressure
Authors: Zhang Duan-zhen , Zhu Xian-yang , Lv Bei , Cui Chun-sheng , Han Xiu-min , Sheng Xiao-tang , Wang Qi-guang , Zhang Po
Published: August 2014

Background—

No method is available to predict whether patients with patent ductus arteriosus (PDA) and severe pulmonary arterial hypertension (PAH) will show persistent postprocedural PAH (PP-PAH) after PDA closure. This study evaluated the usefulness of trial occlusion for predicting PP-PAH after transcatheter PDA closure in patients with severe PAH.

Methods and Results—

Trial occlusion was performed in 137 patients (age ≥12 years) with PDA and severe PAH. All patients undergoing trial occlusion had a mean pulmonary artery pressure ≥45 mm Hg, pulmonary:systemic flow (Qp/Qs) ratio >1.5, and pulmonary:systemic resistance (Rp/Rs) ratio <0.7. A total of 135 patients (98%) showing stable hemodynamics during occlusion trial underwent successful device closure. Linear correlation analysis revealed weak or moderate relationships between the baseline and post-trial pulmonary artery pressures and pulmonary:systemic pressure (Pp/Ps) ratios. Patients were followed up for 1 to 10 years (median: 5 years). PP-PAH (systolic pulmonary artery pressure >50 mm Hg by Doppler echocardiography) was detected in 17 patients (13%), who displayed no significant differences in sex and age compared with patients without PP-PAH. According to discriminant analysis, the strongest discriminators between patients with and without PP-PAH were the baseline left ventricular end-diastolic volume and the baseline and post-trial systolic Pp/Ps ratios. In particular, a post-trial systolic Pp/Ps ratio >0.5 correctly classified 100% of the PP-PAH and non-PAH patients.

Conclusions—

Trial occlusion is a feasible method to predict PP-PAH in patients with PDA and severe PAH. A post-trial systolic Pp/Ps ratio >0.5 indicates a high risk of PP-PAH occurrence after device closure.
Open Transapical Approach to Transcatheter Paravalvular Leakage Closure
Authors: Nijenhuis Vincent J. , Swaans Martin J. , Post Martijn C. , Heijmen Robin H. , de Kroon Thomas L. , ten Berg Jurrien M.
Published: August 2014

Background—

Significant prosthetic paravalvular leakage (PVL) could have serious clinical consequences and impairs survival. Reoperation is associated with a high mortality rate, and transcatheter closure is a new treatment modality for high-risk patients. The goal of this study was to determine safety and midterm clinical efficacy of transcatheter PVL closure using an open transapical approach.

Methods and Results—

All consecutive patients who underwent transcatheter PVL closure in our center were prospectively enrolled. Pre- and postprocedural quality of life and 6-minute walk test were ascertained. All outcomes were defined according to the Valve Academic Research Consortium-2 consensus document. In total, 37 consecutive patients (mean age 67±12 years, 65% male, logistic European System for Cardiac Operative Risk Evaluation 27±17%, Society of Thoracic Surgeons score 7±4%) with severe symptomatic PVL in mitral (81%) or aortic (19%) position underwent transcatheter PVL closure. Procedure success was 86%. Early safety at 30 days (ie, event-free survival) was 84%. The 1-year survival rate was 66%. New York Heart Association functional class and quality of life significantly improved. Clinical efficacy (ie, survival free of stroke, rehospitalization, New York Heart Association 3/4, and device-related dysfunction) was 49% at 3 months and 31% at 1 year. Moderate to severe residual PVL was associated with all-cause mortality (hazard ratio, 3.9; 95% confidence interval, 1.2–12.1;
P
=0.03).

Conclusions—

The open transapical approach to PVL closure in high-risk patients has a high procedural success rate with an acceptable risk of adverse outcomes. This is the first study to prove an increased functional capacity and quality of life after transapical PVL closure. Residual PVL is associated with 1-year mortality.
In-Hospital Switching Between Clopidogrel and Prasugrel Among Patients With Acute Myocardial Infarction Treated With Percutaneous Coronary Intervention
Authors: Bagai Akshay , Wang Yongfei , Wang Tracy Y. , Curtis Jeptha P. , Gurm Hitinder S. , Shah Binita , Cheema Asim N. , Peterson Eric D. , Saucedo Jorge F. , Granger Christopher B. , Roe Matthew T. , Bhatt Deepak L. , McNamara Robert L. , Alexander Karen P.
Published: August 2014

Background—

Although randomized clinical trials have compared clopidogrel with higher potency ADP receptor inhibitors (ADPris) among patients with myocardial infarction, little is known about the frequency and factors associated with switching between ADPris in clinical practice.

Methods and Results—

We studied 47 040 patients with myocardial infarction treated with percutaneous coronary intervention, who received either clopidogrel or prasugrel within 24 hours of admission at 361 US hospitals from July 2009 to June 2011 using the merged Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines and CathPCI Registry database. Hierarchical logistic regression modeling was used to determine factors independently associated with in-hospital ADPri switching. Among 40 531 patients treated initially in-hospital with clopidogrel, 2125 (5.2%) were discharged on prasugrel; this frequency steadily increased from 0% to 7% during the study period. Among 6509 patients treated initially in-hospital with prasugrel, 751 (11.5%) were discharged on clopidogrel. The frequency of this switch increased from 6% to 18% during the first 2 quarters of the study period and decreased to 9% by the end. Switching clopidogrel to prasugrel was associated with high-risk angiographic characteristics (thrombotic, long, and bifurcating lesions), reinfarction in-hospital, and private health insurance coverage. Older age, previous cerebrovascular event, in-hospital coronary artery bypass grafting, in-hospital bleeding, and warfarin use at discharge were associated with switching prasugrel to clopidogrel.

Conclusions—

Clopidogrel and prasugrel are not uncommonly switched in-hospital in patients with myocardial infarction undergoing percutaneous coronary intervention. In contemporary US practice, in addition to risk for bleeding and recurrent ischemic events, medical drug coverage is a major determinant of ADPri selection.
Temporal Trends in Patient Characteristics and Outcomes Among Medicare Beneficiaries Undergoing Primary Prevention Implantable Cardioverter-Defibrillator Placement in the United States, 2006–2010
Authors: Borne Ryan T. , Peterson Pamela N. , Greenlee Robert , Heidenreich Paul A. , Wang Yongfei , Curtis Jeptha P. , Tzou Wendy S. , Varosy Paul D. , Kremers Mark S. , Masoudi Frederick A.
Published: August 2014

Background—

Contemporary patterns of use and outcomes of implantable cardioverter-defibrillators (ICDs) in community practice settings are not well characterized. We assessed temporal trends in patient characteristics and outcomes among older patients undergoing primary prevention ICD therapy in US hospitals between 2006 and 2010.

Methods and Results—

Using the National Cardiovascular Data Registry’s ICD Registry, we identified Medicare fee-for-service beneficiaries aged ≥65 years and older with left ventricular ejection fraction ≤35% who underwent primary prevention ICD implantation, including those receiving concomitant cardiac resynchronization therapy between 2006 and 2010 and could be matched to Medicare claims. Outcomes were mortality and hospitalization (all-cause and heart failure) at 180 days, and device-related complications. We used multivariable hierarchical logistic regression to assess temporal trends in outcomes accounting for changes in patient, physician, and hospital characteristics. The cohort included 117 100 patients. Between 2006 and 2010, only modest changes in patient characteristics were noted. Fewer single lead devices and more cardiac resynchronization therapy devices were used over time. Between 2006 and 2010, there were significant improvements in all outcomes, including 6-month all cause mortality (7.1% in 2006, 6.5% 2010; adjusted odds ratio, 0.88; 95% confidence interval, 0.82–0.95), 6-month rehospitalization (36.3% in 2006, 33.7% in 2010; adjusted odds ratio, 0.87; 95% confidence interval, 0.83–0.91), and device-related complications (5.8% in 2006, 4.8% in 2010; adjusted odds ratio, 0.80; 95% confidence interval, 0.74–0.88).

Conclusions—

The clinical characteristics of this national population of Medicare patients undergoing primary prevention ICD implantation were stable between 2006 and 2010. Simultaneous improvements in outcomes suggest meaningful advances in the care for this patient population.
Ischemic Cardiomyopathy is Associated With Coronary Plaque Progression and Higher Event Rate in Patients After Cardiac Transplantation
Authors: Guddeti Raviteja R. , Matsuo Yoshiki , Matsuzawa Yasushi , Aoki Tatsuo , Lennon Ryan J. , Lerman Lilach O. , Kushwaha Sudhir S. , Lerman Amir
Published: August 2014

Background

Cardiac allograft vasculopathy is the leading cause of graft failure and death in heart transplant (
HT
x) recipients; however, the association between the etiology of heart failure (ischemic cardiomyopathy [
ICM
] or non‐
ICM
) that led to
HT
x and progression of c
ardiac allograft vasculopathy
, and adverse events after
HT
x has not been explored.

Methods and Results

We retrospectively included 165
HT
x patients, who were followed‐up with at least 2 virtual histology–intravascular ultrasound examinations after
HT
x, and grouped them as
ICM
(n=46) or non‐
ICM
(n=119). Coronary artery plaque volume was analyzed using virtual histology–intravascular ultrasound, and cardiovascular event data—a composite of myocardial infarction, hospitalization for heart failure and arrhythmia, revascularization, retransplantation, and death including cardiovascular death—were collected from the medical records of all study subjects.
ICM
patients had significantly higher plaque volume at both first (
P
=0.040) and follow‐up (
P
=0.015) intravascular ultrasound examinations. After multivariate adjustment for traditional coronary risk factors,
ICM
was significantly associated with plaque progression (odds ratio 3.10;
CI
1.17 to 9.36;
P
=0.023). Ten‐year cardiovascular event‐free survival was 50% in
ICM
patients compared with 84% in non‐
ICM
patients (log‐rank test
P
=0.003). In multivariate Cox proportional hazard analysis,
ICM
was significantly associated with a higher event rate after
HT
x (hazard ratio 2.02; 95%
CI
1.01 to 4.00;
P
=0.048).

Conclusion

Our study demonstrates that ischemic etiology of cardiomyopathy prior to
HT
x may be independently associated with plaque progression and higher event rate after
HT
x.
Learning to Play It Safe (or Not): Stable and Evolving Neural Responses during Adolescent Risky Decision-making
Authors: Kahn Lauren E. , Peake Shannon J. , Dishion Thomas J. , Stormshak Elizabeth A. , Pfeifer Jennifer H.
Published: August 2014

Adolescent decision-making is a topic of great public and scientific interest. However, much of the neuroimaging research in this area contrasts only one facet of decision-making (e.g., neural responses to anticipation or receipt of monetary rewards). Few studies have directly examined the processes that occur immediately before making a decision between two options that have varied and unpredictable potential rewards and penalties. Understanding adolescent decision-making from this vantage point may prove critical to ameliorating risky behavior and improving developmental outcomes. In this study, participants aged 14–16 years engaged in a driving simulation game while undergoing fMRI. Results indicated activity in ventral striatum preceded risky decisions and activity in right inferior frontal gyrus (rIFG) preceded safe decisions. Furthermore, participants who reported higher sensation-seeking and sensitivity to reward and punishment demonstrated lower rIFG activity during safe decisions. Finally, over successive games, rIFG activity preceding risky decisions decreased, whereas thalamus and caudate activity increased during positive feedback (taking a risk without crashing). These results indicate that regions traditionally associated with reward processing and inhibition not only drive risky decision-making in the moment but also contribute to learning about risk tradeoffs during adolescence.
Representational Similarity of Social and Valence Information in the Medial pFC
Authors: Chavez Robert S. , Heatherton Todd F.
Published: August 2014

The human brain is remarkably adept at integrating complex information to form unified psychological representations of agents, objects, and events in the environment. Two domains in which this ability is particularly salient are the processing of social and valence information and are supported by common cortical areas in the medial pFC (MPFC). Because social information is often embedded within valenced emotional contexts, it is possible that activation patterns within the MPFC may represent both of these types of cognitive processes when presented simultaneously. The current study tested this possibility by employing a large-scale automated meta-analysis tool, together with multivoxel pattern analysis to investigate the representational similarity of social and valence information in the MPFC during fMRI. Using a representational similarity analysis, we found a high degree of representational similarity both within social dimensions and within valence dimensions, but not across them (e.g., positive social information was highly dissimilar to negative nonsocial information), in a ventral portion of the MPFC. These results were significantly correlated with a behaviorally measured similarity structure of the same stimuli, suggesting that a psychologically meaningful representation of social and valence information is reflected by multivoxel activation patterns in the ventral MPFC.