bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of Cesarean Scar Pregnancy: A Single-Institution Retrospective Review
Authors: Giampaolino P. , De Rosa N. , Morra I. , Bertrando A. , Di Spiezio Sardo A. , Zizolfi B. , Ferrara C. , Della Corte L. , Bifulco G.
Published: March 2018

Objective. Cesarean scar pregnancy (CSP) is a rare condition that occurs when the pregnancy implants in a cesarean scar. An early diagnosis and a proper management are fundamental to prevent maternal complications. We review and discuss the different treatment employed in our unit to reduce morbidity, preserve fertility, and predict possible complications. Methods. The reported treatment has been expectant management, operative hysteroscopy approach, and intramuscular injection of 50 mg methotrexate (MTX), followed by cervical dilation and manual vacuum aspiration (D&S) with a Karman cannula under ultrasound guidance, uterine artery embolization (UAE), and manual vacuum aspiration under ultrasound guidance and uterine artery embolization before surgical laparotomic resection. Results. Complications were more frequent in women with a history of three or more cesarean section deliveries and with a myometrial thickness thinner than 2 mm. MTX and D&S treatment appear to be most effective and safe at the early age of pregnancy, while UAE and D&S are related to the highest risk of complication in any age of pregnancy. Conclusion. An appropriate preoperative diagnostic evaluation, the identification of cases at higher risk, and those eligible for a conservative treatment are fundamental to reduce complications.
Safety and Efficacy of Triple Therapeutic Targets with Rivaroxaban after Acute Myocardial Infarction Complicated by Left Ventricular Thrombi in a Case of Nonvalvular Atrial Fibrillation
Authors: Summaria Francesco , Sgueglia Gregory A. , D’Errico Fabrizio , De Santis Antonella , Piccioni Fabiana , Gioffrè Gaetano , Gaspardone Achille
Published: March 2018

We present the complex case of a high-risk patient with nonvalvular atrial fibrillation, who experienced a non-ST elevation myocardial infarction complicated by left ventricular (LV) thrombi and underwent percutaneous coronary intervention with drug-eluting stent implantation. The patient was initially treated with short-term triple therapy including aspirin, clopidogrel, and rivaroxaban 15 mg/die. Following aspirin dropping one month after discharge, the patient continued on dual therapy with clopidogrel and rivaroxaban, and a clinical and imaging follow-up at 6 and 12 months confirmed the LV thrombi resolution, with no thromboembolic episodes and a good safety profile.
Research on the Multilayer Free Damping Structure Design
Authors: Meng Jie , Sun Dagang
Published: March 2018

The aim of this paper is to put forward a design model for multilayer free damping structures. It sets up a mathematical model and deduces the formula for its structural loss factor η and analyzes the change rules of η along with the change rate of the elastic modulus ratio q1, the change rate of the loss factors of damping materials q2, and the change rate of the layer thickness ratio q3 under the condition with the layer thickness ratio h2 = 1,3, 5,10 by software MATLAB. Based on three specific damping structures, the mathematical model is verified through ABAQUS. With the given structural loss factor (η ≥ 2) and the layer number (n = 3, 4,5, 6), 34 kinds of multilayer free damping structures are then presented. The study is meant to provide a more flexible and more diverse design solution for multilayer free damping structures.
Efficacy, Safety, and Quality of Treatment Satisfaction of Premixed Human and Analogue Insulin Regimens in a Large Cohort of Type 2 Diabetic Patients: PROGENS BENEFIT Observational Study
Authors: Nabrdalik Katarzyna , Kwiendacz Hanna , Sawczyn Tomasz , Tomasik Andrzej , Kukla Michał , Masierek Małgorzata , Gumprecht Janusz
Published: March 2018

Diabetes is a lifelong course disease, so insulin treatment has to be effective and safe, and patients should be satisfied with it. We aimed to compare efficacy, safety, and quality of treatment satisfaction of human and premixed analogue insulin among 3264 patients (53.58% women) with type 2 diabetes mellitus (T2DM) in a real-life environment. 2493 patients (62.77%) had been assigned to group I where before the inclusion into the study the treatment regimen has been changed from analogue to human premixed insulin and 771 patients (37.23%) to group II where the treatment with insulin analogue remained unchanged. At the end of the study, there was a reduction of HbA1c observed in both of the groups; however, Δ HbA1c was significantly higher in group 1 (−0.599 versus −0.406; P<0.001 at visit 3 versus visit 1). The number of hypoglycemic episodes during the study observation was insignificantly reduced in both groups. Diabetes treatment satisfaction measured with DTSQ increased at the end of the study and was significantly better in group I compared to group II (P<0.001). This observational study proved that both human and premixed analogue insulin are effective and safe, and patients are satisfied with the treatment.
Multiclass Classification of Cardiac Arrhythmia Using Improved Feature Selection and SVM Invariants
Authors: Mustaqeem Anam , Anwar Syed Muhammad , Majid Muahammad
Published: March 2018

Arrhythmia is considered a life-threatening disease causing serious health issues in patients, when left untreated. An early diagnosis of arrhythmias would be helpful in saving lives. This study is conducted to classify patients into one of the sixteen subclasses, among which one class represents absence of disease and the other fifteen classes represent electrocardiogram records of various subtypes of arrhythmias. The research is carried out on the dataset taken from the University of California at Irvine Machine Learning Data Repository. The dataset contains a large volume of feature dimensions which are reduced using wrapper based feature selection technique. For multiclass classification, support vector machine (SVM) based approaches including one-against-one (OAO), one-against-all (OAA), and error-correction code (ECC) are employed to detect the presence and absence of arrhythmias. The SVM method results are compared with other standard machine learning classifiers using varying parameters and the performance of the classifiers is evaluated using accuracy, kappa statistics, and root mean square error. The results show that OAO method of SVM outperforms all other classifiers by achieving an accuracy rate of 81.11% when used with 80/20 data split and 92.07% using 90/10 data split option.
Dynamic Response Simulation of Lining Structure for Tunnel Portal Section under Seismic Load
Authors: Liu Guoqing , Chen Juntao , Xiao Ming , Yang Yang
Published: March 2018

Portal section is the weak link of seismic fortification for tunnel structure. Assuming that seismic wave is the vertical incident elastic plane wave, the plane wave input method for the portal section was discussed in this paper; that is, the wave input problem can be converted to the problem of calculating equivalent nodal force at artificial boundaries. Based on different damage evolution processes of concrete under tension and compression conditions, the tension and compression damage variables were defined and solved, respectively. And then a simple elastic dynamic damaged constitutive model for concrete lining was built. According to the characteristics of dynamic interaction between the lining and rock, and based on the dynamic contact force algorithm, an analytical model for joint loading between the lining and rock was built. This model can simulate lining features such as bond, separation, and slip under seismic load. The dynamic response characteristics of lining structure for the portal section under seismic load were analyzed by taking example for an exit section of Dianzhong diversion project in strong earthquake area. The results show that the relative displacement magnitudes of the lining parts are related to the vibration direction of the seismic wave, and the peak displacements decrease gradually to the fixed values from the portal to the interior. The damage coefficients of the lining parts accumulate gradually over time, and the farther the lining is away from the portal, the less serious the seismic damage is. The separation and slip zone distributions of the lining are basically consistent with its severe seismic damage area, which are mainly at haunch, spandrel, and arch foot within a certain range of distance from the portal. The seismic fortified length and key fortified parts of tunnel structure for the portal section can be determined according to the calculation results.
Prevention and Management of Complications in Laparoscopic Myomectomy
Authors: Tanos V. , Berry K. E. , Frist M. , Campo R. , DeWilde R. L.
Published: March 2018

Myomectomy aims to preserve fertility, treat abnormal uterine bleeding, and alleviate pain. It should cause minimal damage to the endometrium, while being tolerable and durable, and reduce the incidence of myoma recurrence and complications including bleeding, hematoma, adhesions, and gravid uterus perforation. Training and experience are crucial to reduce complications. The surgical strategy depends on imaging information on the myomas. The position of the optical and secondary ports will determine the degree of ergonomic surgery performance, time and difficulty of myoma enucleation, and the suturing quality. Appropriate hysterotomy length relative to myoma size can decrease bleeding, coagulation, and suturing times. Bipolar coagulation of large vessels, while avoiding carbonization and myometrium gaps after suturing, may decrease the risk of myometrial hematoma. Quality surgery and the use of antiadhesive barriers may reduce the risk of postoperative adhesions. Slow rotation of the beveled morcellator and good control of the bag could reduce de novo myoma and endometriosis. Low intra-abdominal CO2 pressure may reduce the risk of benign and malignant cell dissemination. The benefits a patient gains from laparoscopic myomectomy are greater than the complication risks of laparoscopic morcellation. Recent publications on laparoscopic myomectomies demonstrate reduced hospitalization stays, postoperative pain, blood loss, and recovery compared to open surgery.
Improved Multiscale Entropy Technique with Nearest-Neighbor Moving-Average Kernel for Nonlinear and Nonstationary Short-Time Biomedical Signal Analysis
Authors: Arunachalam S. P. , Kapa S. , Mulpuru S. K. , Friedman P. A. , Tolkacheva E. G.
Published: March 2018

Analysis of biomedical signals can yield invaluable information for prognosis, diagnosis, therapy evaluation, risk assessment, and disease prevention which is often recorded as short time series data that challenges existing complexity classification algorithms such as Shannon entropy (SE) and other techniques. The purpose of this study was to improve previously developed multiscale entropy (MSE) technique by incorporating nearest-neighbor moving-average kernel, which can be used for analysis of nonlinear and non-stationary short time series physiological data. The approach was tested for robustness with respect to noise analysis using simulated sinusoidal and ECG waveforms. Feasibility of MSE to discriminate between normal sinus rhythm (NSR) and atrial fibrillation (AF) was tested on a single-lead ECG. In addition, the MSE algorithm was applied to identify pivot points of rotors that were induced in ex vivo isolated rabbit hearts. The improved MSE technique robustly estimated the complexity of the signal compared to that of SE with various noises, discriminated NSR and AF on single-lead ECG, and precisely identified the pivot points of ex vivo rotors by providing better contrast between the rotor core and the peripheral region. The improved MSE technique can provide efficient complexity analysis of variety of nonlinear and nonstationary short-time biomedical signals.
Salivary Markers and Microbial Flora in Mouth Breathing Late Adolescents
Authors: Mummolo Stefano , Nota Alessandro , Caruso Silvia , Quinzi Vincenzo , Marchetti Enrico , Marzo Giuseppe
Published: March 2018

Objective. This is a 6-month observational case-control study that aims to estimate plaque index (PI), salivary flow, buffering capacity of saliva, and specific Streptococcus mutans (S. mutans) and Lactobacillus rates in a mouth breathing late adolescents sample, after a professional oral hygiene procedure and home oral hygiene instructions. Subjects and Methods. A sample of 20 mouth breathing late adolescents/young adults (average: 19.2±2.5; range: 18–23 years) and a matched control group of nose breathing subjects (average: 18.3±3.2; range 18–23 years) were included in the study. All the participants were subjected to a professional oral hygiene procedure and appropriate home oral hygiene instructions (t0). After three months (t1) and six months (t2), the PI, salivary flow, buffering capacity of saliva, and S. mutans and Lactobacilli rates were recorded. Results. The mean buffering capacity of saliva and the salivary flow rate showed no significant difference between the two groups, all over the observational period. For PI, a significantly higher mode (score 1 of PI) was observed in the study group at t1 (score 0 = 35% of subjects; score 1 = 60%; score 2 = 5%) and t2 (score 1 = 65% of subjects, score 2 = 35%), with respect to control group. Furthermore, mouth breathing subjects show a significant 4 times higher risk to develop S. mutans CFU > 105 (CI lower limit: 0.95; CI upper limit: 9.48; chi-square: 4.28; p=0.03), with respect to the control subjects. Conclusions. Mouth breathing late adolescents show a significantly higher risk to develop S. mutans CFU > 105 and an increased level of PI. Interceptive orthodontic treatments in growing subjects, like palatal expansion, are encouraged to improve the nasal air flow. In older subjects, orthodontic treatments should be performed with removable appliances like clear aligners, in order to allow a better oral hygiene level.
Phase II Study of the Dual EGFR/HER3 Inhibitor Duligotuzumab (MEHD7945A) versus Cetuximab in Combination with FOLFIRI in Second-Line RAS Wild-Type Metastatic Colorectal Cancer
Authors: Hill Andrew G. , Findlay Michael P. , Burge Matthew E. , Jackson Christopher , Alfonso Pilar Garcia , Samuel Leslie , Ganju Vinod , Karthaus Meinolf , Amatu Alessio , Jeffery Mark , Bartolomeo Maria Di , Bridgewater John , Coveler Andrew L. , Hidalgo Manuel , Kapp Amy V. , Sufan Roxana I. , McCall Bruce B. , Hanley William D. , Penuel Elicia M. , Pirzkall Andrea , Tabernero Josep
Published: March 2018

Purpose: Duligotuzumab is a dual-action antibody directed against EGFR and HER3.

Experimental Design: Metastatic colorectal cancer (mCRC) patients with KRAS ex2 wild-type received duligotuzumab or cetuximab and FOLFIRI until progression or intolerable toxicity. Mandatory tumor samples underwent mutation and biomarker analysis. Efficacy analysis was conducted in patients with RAS exon 2/3 wild-type tumors.

Results: Of 134 randomly assigned patients, 98 had RAS ex2/3 wild-type. Duligotuzumab provided no progression-free survival (PFS) or overall survival (OS) benefit compared with cetuximab, although there was a trend for a lower objective response rate (ORR) in the duligotuzumab arm. No relationship was seen between PFS or ORR and ERBB3, NRG1, or AREG expression. There were fewer skin rash events for duligotuzumab but more diarrhea. Although the incidence of grade ≥3 AEs was similar, the frequency of serious AEs was higher for duligotuzumab.

Conclusions: Duligotuzumab plus FOLFIRI did not appear to improve the outcomes in patients with RAS exon 2/3 wild-type mCRC compared with cetuximab + FOLFIRI. Clin Cancer Res; 24(10); 2276–84. ©2018 AACR.
Red Cell Alloantibody Screening: Comparative Analysis of Three Different Technologies
Authors: Orlando Nicoletta , Bianchi Maria , Valentini Caterina Giovanna , Maresca Maddalena , Massini Giuseppina , Putzulu Rossana , Zini Gina , Teofili Luciana
Published: March 2018

Background: The detection of irregular antibody is a critical issue in the management of red blood cell transfusion according to the Type & Screen (T&S) practice. In order to implement the T&S procedure at our blood bank, we compared three different automated analyzers based on column agglutination technique (CAT) or solid phase red cell adherence assay (SPACA) methods. Methods: Pre-transfusion antibody screening was performed in 986 patients candidate to elective surgery at low risk for red blood cell transfusion. We tested the following kits: the three-cell panel micro-CAT system ID-DiaCell I-II-III (DiaMed), the four-cell panel solid-phase system Capture-R Ready Screen-4 (Immucor), and the four-cell panel micro-CAT system Serascan Diana-4 (Grifols). Positive results were further investigated using corresponding identification panels, and discrepant results were investigated with all the antibody identification systems. Results: Among 986 samples, we observed 967 concordant negative results (98.1%), 8 concordant positive results (0.8% of cases), and 11 discrepant results (1.1%). Among discrepant samples, an alloantibody could been identified in two patents (anti-M, detected by Serascan Diana-4 and ID-DiaCell I, II, III; anti-Kpa, detected by Capture-R Ready Screen-4 and Serascan Diana-4). Conclusion: Among the evaluated technologies, the four-cell panel micro-CAT system displayed the highest sensitivity and specificity with an optimal negative predictive value. These features might be relevant to the routine implementation of the T&S transfusion strategy.
Clinical Diagnosis of Dental Caries in the 21st Century: Introductory Paper – ORCA Saturday Afternoon Symposium, 2016
Authors: Machiulskiene Vita , Carvalho Joana Christina
Published: March 2018

Classifications employed to measure dental caries should first of all reflect the dynamics of the disease, in order to provide a solid basis for subsequent treatment decisions and for further monitoring of dental health of individual patients and populations. The contemporary philosophy of dental caries management implies that nonoperative treatment of caries lesions should be implemented whenever possible, limiting operative interventions to the severe and irreversible cases. The ORCA Saturday Afternoon Symposium 2016, held back-to-back to the 63rd ORCA Congress in Athens, Greece, was intended to provide an update on general requirements for clinical caries diagnosis and to overview caries diagnostic classifications including their rationale, validation, advantages, and limitations. Clinical caries diagnostic criteria and caries management outcomes are interrelated, and any diagnostic classification disregarding this concept is outdated, according to the current understanding of oral health care. Choosing clinical caries diagnostic classifications that assess the activity status of detected lesions should be a priority for dental professionals since these classifications favor the best clinical practice directed towards nonoperative interventions. The choice of clinical caries diagnostic classifications in research, in clinical practice, and in public health services should be guided by the best available scientific evidence. The clinical caries diagnostic classifications should be universally applicable in all these fields. Policy making in oral health care and the underlying policy analyses should follow the same standards. Any clinical caries diagnostic classification disregarding the universality of its use is of limited or no interest in the context of the clinical caries diagnosis of today.
Drug Resistance-Associated Mutations in Antiretroviral Treatment-Experienced Patients in Kuwait
Authors: Chehadeh Wassim , Albaksami Osama , John Sonia Elezebeth , Al-Nakib Widad
Published: March 2018

Objectives: To investigate the prevalence of nonpolymorphic resistance-associated mutations (RAM) in HIV-1 patients on first-line antiretroviral therapy in Kuwait. Subjects and Methods: Total RNA was isolated from plasma samples of 42 patients who received a first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. HIV-1 protease and reverse transcriptase genetic regions were then amplified by nested reverse transcription-polymerase chain reaction and directly sequenced. The HIV-1 subtype was identified using the Bayesian phylogenetic method, and RAM were identified using the Stanford University genotypic resistance interpretation algorithm. Results: The HIV-1 viral load at sampling ranged from < 20 to 8.25 × 104 copies/ml. CRF01_AE, C, and B were the most predominant HIV-1 subtypes. Nonpolymorphic mutations associated with resistance to antiretroviral drugs were detected in 11 (26.2%) of the 42 patients; 5 (11.9%) patients had mutations associated with a high-level resistance to nucleoside reverse transcriptase inhibitors (NRTI), 4 (9.5%) patients had mutations associated with resistance to NNRTI, 1 (2.4%) patient had mutations associated with resistance to both NRTI and NNRTI, and 1 (2.4%) patient had mutations potentially associated with low-level resistance to both protease inhibitors and NNRTI. All patients with RAM had a detectable plasma HIV-1 RNA level. Conclusion: Our results indicate the development of RAM during an NNRTI-based regimen and highlight the importance of considering other regimens to avoid treatment failure.
NG2-Glia, a New Player in Energy Balance
Authors: Robins Sarah C. , Kokoeva Maia V.
Published: March 2018

There is increasing evidence that glia act not only as neuronal support cells, but that they can also influence physiological outcomes via effects on neural signalling. The role of NG2-glia in this regard is especially enigmatic, as they are known to interact with neural circuits but their precise functions other than as oligodendrocyte progenitor cells remain elusive. Here, we summarise recent evidence suggesting that NG2-glia play a role in the maintenance of energy homeostasis, most notably via the support of leptin-sensing neural circuits. We also discuss the potential clinical implication of these findings specifically in the context of cranial radiation therapy.
Estudo Comparado do Turismo no Espaço Rural: Coredes de Campos de Cima da Serra e Fronteira Oeste, RS, Brasil
Authors: Valentini Andiara de Souza , Santos Eurico de Oliveira , Vianna Silvio Luiz Gonçalves , Thomé-Ortiz Humberto
Published: March 2018

Com as grandes mudanças ocorridas no meio rural, fez-se necessário a inclusão das atividades não agrícolas para o incremento da renda familiar. Como atividade paralela, o turismo vem auxiliando as famílias a aumentar seus rendimentos e diversificar as suas atividades. Partindo dessa premissa, foi realizado um estudo comparado do turismo no espaço rural nos Conselhos Regionais de Desenvolvimento (Coredes) Campos de Cima da Serra e Fronteira Oeste, no estado do Rio Grande do Sul, Brasil. A pesquisa foi dividida em duas fases, a primeira, de caráter exploratório, onde se realizou o levantamento do número das propriedades rurais ativas, que recebiam turistas. No segundo momento, todas as propriedades foram visitadas para aplicação de um questionário, com perguntas abertas e fechadas. Os dados foram coletados em 20 propriedades rurais, entre dezembro de 2013 e janeiro de 2014. O objetivo central deste estudo foi comparar as potencialidades das propriedades rurais, visando compreender sua importância e sua influência para o desenvolvimento do turismo no espaço rural, de maneira a torná-lo uma alternativa econômica efetiva. Concluiu-se que o agroturismo é a atividade que se sobressai nos Coredes Campos de Cima da Serra e Fronteira, uma vez que a principal atividade econômica das propriedades rurais é a atividade primária, ficando o turismo como uma receita complementar a renda familiar.
Direito Internacional e Turismo: uma introdução
Authors: Santos Alberto Pereira dos , Brant Danielle , Brant Rosa Maria
Published: March 2018

Este artigo tem como objetivo refletir acerca das interfaces entre o turismo e o direito internacional. O direito, como instrumento regulador dos conflitos sociais, mostra-se presente neste processo sob o aspecto do direito internacional do turismo, acrescido das diretivas dos tratados assinados pelo Brasil que firmam disposição relativa ao turismo. Utilizou-se como método a reflexão teórica e a revisão bibliográfica a partir de algumas referências da doutrina jurídica que tratam do direito internacional e de sua relação com o turismo. Os resultados deste trabalho indicam que há intrínseca relação entre o direito internacional e o turismo face ao avanço dos meios de transportes, do processo de globalização com internacionalização da economia e da cultura e, sobretudo, da expansão dos direitos humanos e de sua proteção pelos organismos de direito internacional. A conclusão do estudo indica que há escassez de produção teórica acerca desta temática, em parte pelos profissionais do direito e em parte por estudiosos do turismo. Nesse contexto, o artigo se insere como sucinta contribuição ao debate no meio acadêmico.
Glucose-Lowering Therapies and Heart Failure in Type 2 Diabetes Mellitus
Authors: Vijayakumar Shilpa , Vaduganathan Muthiah , Butler Javed
Published: March 2018

Diabetes mellitus independently increases the risk of and mortality from heart failure in a manner that is well established but inadequately understood. Glycemic optimization does not eliminate this risk, and measures of glycemic control are insufficient markers of cardiovascular risk. In response to a regulatory guidance from the US Food and Drug Administration, glucose-lowering agents are now routinely evaluated in large cardiovascular outcome trials. These recent trial experiences of novel and established glucose-lowering therapies have shown variable risks and benefits with respect to heart failure. Cardiovascular outcome trials have increasingly included heart failure events as either a component of the primary end point or a secondary adjudicated end point. We comprehensively review each established and novel currently marketed glucose-lowering therapy, their biological targets, mechanisms of action, and relationships with heart failure. We then highlight gaps in available evidence and directions for future research regarding the ascertainment of heart failure-related data in the evaluation of emerging glucose-lowering therapies.
Relation of Dietary Sodium (Salt) to Blood Pressure and Its Possible Modulation by Other Dietary Factors
Authors: Stamler Jeremiah , Chan Queenie , Daviglus Martha L. , Dyer Alan R. , Van Horn Linda , Garside Daniel B. , Miura Katsuyuki , Wu Yangfeng , Ueshima Hirotsugu , Zhao Liancheng , Elliott Paul
Published: March 2018

Available data indicate that dietary sodium (as salt) relates directly to blood pressure (BP). Most of these findings are from studies lacking dietary data; hence, it is unclear whether this sodium–BP relationship is modulated by other dietary factors. With control for multiple nondietary factors, but not body mass index, there were direct relations to BP of 24-hour urinary sodium excretion and the urinary sodium/potassium ratio among 4680 men and women 40 to 59 years of age (17 population samples in China, Japan, United Kingdom, and United States) in the INTERMAP (International Study on Macro/Micronutrients and Blood Pressure), and among its 2195 American participants, for example, 2 SD higher 24-hour urinary sodium excretion (118.7 mmol) associated with systolic BP 3.7 mm Hg higher. These sodium–BP relations persisted with control for 13 macronutrients, 12 vitamins, 7 minerals, and 18 amino acids, for both sex, older and younger, blacks, Hispanics, whites, and socioeconomic strata. With control for body mass index, sodium–BP—but not sodium/potassium–BP—relations were attenuated. Normal weight and obese participants manifested significant positive relations to BP of urinary sodium; relations were weaker for overweight people. At lower but not higher levels of 24-hour sodium excretion, potassium intake blunted the sodium–BP relation. The adverse association of dietary sodium with BP is minimally attenuated by other dietary constituents; these findings underscore the importance of reducing salt intake for the prevention and control of prehypertension and hypertension.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00005271.
Temporal Trends of High‐Intensity Statin Therapy Among Veterans Treated With Percutaneous Coronary Intervention
Authors: Bin Abdulhak Aref A. , Vaughan‐Sarrzin Mary , Kaboli Peter , Horwitz Phillip A. , Mosher Hilary , Sigurdsson Gardar , Walker Nicholas E. , Wallace Robert , Robinson Jennifer G.
Published: March 2018

Background

The 2013 American College of Cardiology/American Heart Association blood cholesterol guideline recommends high‐intensity statin therapy among certain groups of patients, but full implementation of the guideline has not yet been satisfactory. We aimed to investigate the temporal trends and predictors of high‐intensity statin therapy among veterans who had been treated with percutaneous coronary intervention (
PCI
) and followed up by cardiologists within the Veterans Health Administrative system.

Methods and Results

A retrospective cohort study was conducted at the Veterans Health Administrative system including all patients >18 years old who had their
PCI
procedure between October 2010 and September 2016. National Veterans Health Administrative databases were used to retrieve study participant's demographics, comorbid conditions, statin type and dose within 90 days before and after the
PCI
procedure. There were 48 862 patients who underwent a
PCI
procedure during the study period. High‐intensity statin use at 90 days post‐
PCI
rose from 23% in 2010 to 37% before release of the 2013 American College of Cardiology/American Heart Association cholesterol guideline, then rose sharply to 80% by 2016. The projected 10‐year risk of arteriosclerotic cardiovascular disease events among our study population was projected to be ≈1841 fewer if the cohort had received high‐intensity statin therapy versus moderate‐intensity statin.

Conclusions

By 2016, the 2013 American College of Cardiology/American Heart Association blood cholesterol guideline was well implemented among veterans who had a
PCI
procedure in the Veterans Health Administrative system, suggesting systems of care can be improved to increase rates of high‐intensity statin initiation.
Oligomerization of Paramagnetic Substrates Result in Signal Amplification and Can be Used for MR Imaging of Molecular Targets
Authors: Bogdanov Alexei , Matuszewski Lars , Bremer Christoph , Petrovsky Alexander , Weissleder Ralph
Published: March 2018

Magnetic resonance imaging (MRI) has evolved into a sophisticated, noninvasive imaging modality capable of high-resolution anatomical and functional characterization of transgenic animals. To expand the capabilities MRI, we have developed a novel MR signal amplification (MRamp) strategy based on enzyme-mediated polymerization of paramagnetic substrates into oligomers of higher magnetic relaxivity. The substrates consist of chelated gadolinium covalently bound to phenols, which then serve as electron donors during enzymatic hydrogen peroxide reduction by peroxidase. The converted monomers undergo rapid condensation into paramagnetic oligomers leading to a threefold increase in atomic relaxivity ( R1/Gd). The observed relaxivity changes are largely due to an increase in the rotational correlation time τr of the lanthanide. Three applications of the developed system are demonstrated: (1) imaging of nanomolar amounts of an oxidoreductase (peroxidase); (2) detection of a model ligand using an enzyme-linked immunoadsorbent assay format; and (3) imaging of E-selectin on the surface of endothelial cells probed for with an anti-E-selectin – peroxidase conjugate. The development of “enzyme sensing” probes is expected to have utility for a number of applications including in vivo detection of specific molecular targets. One particular advantage of the MRamp technique is that the same paramagnetic substrate can be potentially used to identify different molecular targets by attaching enzymes to various antibodies or other target-seeking molecules.
Conventional and High-Speed Intravital Multiphoton Laser Scanning Microscopy of Microvasculature, Lymphatics, and Leukocyte-Endothelial Interactions
Authors: Padera Timothy P. , Stoll Brian R. , So Peter T.C. , Jain Rakesh K.
Published: March 2018

The ability to determine various functions of genes in an intact host will be an important advance in the postgenomic era. Intravital imaging of gene regulation and the physiological effect of the gene products can play a powerful role in this pursuit. Intravital epifluorescence microscopy has provided powerful insight into gene expression, tissue pH, tissue pO2, angiogenesis, blood vessel permeability, leukocyte-endothelial (L-E) interaction, molecular diffusion, convection and binding, and barriers to the delivery of molecular and cellular medicine. Multiphoton laser scanning microscopy (MPLSM) has recently been applied in vivo to overcome three drawbacks associated with traditional epifluorescence microscopy: (i) limited depth of imaging due to scattering of excitation and emission light; (ii) projection of three-dimensional structures onto a two-dimensional plane; and (iii) phototoxicity. Here, we use MPLSM for the first time to obtain high-resolution images of deep tissue lymphatic vessels and show an increased accuracy in quantifying lymphatic size. We also demonstrate the use of MPLSM to perform accurate calculations of the volume density of angiogenic vessels and discuss how this technique may be used to assess the potential of antiangiogenic treatments. Finally, high-speed MPLSM, applied for the first time in vivo, is used to compare L-E interactions in normal tissue and a rhabdomyosarcoma tumor. Our work demonstrates the potential of MPLSM to noninvasively monitor physiology and pathophysiology both at the tissue and cellular level. Future applications will include the use of MPLSM in combination with fluorescent reporters to give novel insight into the regulation and function of genes.
Molecular Imaging of Gene Expression and Efficacy following Adenoviral-Mediated Brain Tumor Gene Therapy
Authors: Rehemtulla Alnawaz , Hall Daniel E. , Stegman Lauren D. , Prasad Uttara , Chen Grace , Bhojani Mahaveer Swaroop , Chenevert Thomas L. , Ross Brian D.
Published: March 2018

Cancer gene therapy is an active area of research relying upon the transfer and subsequent expression of a therapeutic transgene into tumor cells in order to provide for therapeutic selectivity. Noninvasive assessment of therapeutic response and correlation of the location, magnitude, and duration of transgene expression in vivo would be particularly useful in the development of cancer gene therapy protocols by facilitating optimization of gene transfer protocols, vector development, and prodrug dosing schedules. In this study, we developed an adenoviral vector containing both the therapeutic transgene yeast cytosine deaminase (yCD) along with an optical reporter gene (luciferase). Following intratumoral injection of the vector into orthotopic 9L gliomas, anatomical and diffusion-weighted MR images were obtained over time in order to provide for quantitative assessment of overall therapeutic efficacy and spatial heterogeneity of cell kill, respectively. In addition, bioluminescence images were acquired to assess the duration and magnitude of gene expression. MR images revealed significant reduction in tumor growth rates associated with yCD/5-fluorocytosine (5FC) gene therapy. Significant increases in mean tumor diffusion values were also observed during treatment with 5FC. Moreover, spatial heterogeneity in tumor diffusion changes were also observed revealing that diffusion magnetic resonance imaging could detect regional therapeutic effects due to the nonuniform delivery and/or expression of the therapeutic yCD transgene within the tumor mass. In addition, in vivo bioluminescence imaging detected luciferase gene expression, which was found to decrease over time during administration of the prodrug providing a noninvasive surrogate marker for monitoring gene expression. These results demonstrate the efficacy of the yCD/5FC strategy for the treatment of brain tumors and reveal the feasibility of using multimodality molecular and functional imaging for assessment of gene expression and therapeutic efficacy.
In Vitro and In Vivo Characterization of a Dual-Function Green Fluorescent Protein–HSV1-Thymidine Kinase Reporter Gene Driven by the Human Elongation Factor 1α Promoter
Authors: Luker Gary D. , Luker Kathryn E. , Sharma Vijay , Pica Christina M. , Dahlheimer Julie L. , Ocheskey Joe A. , Fahrner Timothy J. , Milbrandt Jeffrey , Piwnica-Worms David
Published: March 2018

Toward the goal of monitoring activity of native mammalian promoters with molecular imaging techniques, we stably transfected DU145 prostate carcinoma cells with a fusion construct of enhanced green fluorescent protein (EGFP) and wild-type herpes simplex virus-1 thymidine kinase (HSV1-TK) as a reporter gene driven by the promoter for human elongation factor 1α (EF-1α-EGFP-TK). Using this model system, expression of EGFP was quantified by flow cytometry and fluorescence microscopy, while the HSV1-TK component of the reporter was quantified with 8-[3H]ganciclovir (8-[3H]GCV). As analyzed by flow cytometry, passage of EGFP-TK-DU145 transfected cells (ETK) in vitro resulted in populations of cells with high and low expression of EGFP over time. High and low ETK cells retained 23-fold and 5-fold more GCV, respectively, than control. While differences in uptake and retention of GCV corresponded to relative expression of the reporter gene in each subpopulation of cells as determined by both flow cytometry (EGFP) and quantitative RT-PCR, the correlation was not linear. Furthermore, in high ETK cells, net retention of various radiolabeled nucleoside analogues varied; the rank order was 8-[3H]GCV < 9-(4-fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG) ≈ 8-[3H]penciclovir (8-[3H]PCV) < 2′-fluoro-2′-deoxy-5-iodouracil-beta-d-arabinofuranoside (2-[14C]FIAU). Xenograft tumors of ETK cells in vivo accumulated 2.5-fold more 8-[3H]GCV per gram of tissue and showed greater fluorescence from EGFP than control DU145 cells, demonstrating that the reporter gene functioned in vivo. These data extend previous reports by showing that a human promoter can be detected in vitro and in vivo with a dual-function reporter exploiting optical and radiotracer techniques.
Evaluation of 2′-Deoxy-2′-Flouro-5-Methyl-1-β-d-Arabinofuranosyluracil as a Potential Gene Imaging Agent for HSV-tk Expression In Vivo
Authors: Alauddin Mian M. , Shahinian Atranik , Gordon Erlinda M. , Conti Peter S.
Published: March 2018

2′-Deoxy-2′-flouro-5-methyl-1-β-d-arabinofuranosyluracil (FMAU) has been evaluated in HT-29 cells as a potential positron emission tomography (PET) radiotracer for imaging HSV-tk gene expression in vivo. In vitro experiments demonstrate that the accumulation of [14C]-FMAU in HSV-tk-expressing cells is 2.4-fold ( p < .02), 4.0-fold ( p < .001), and 5.3-fold ( p < .001) higher than the wild-type cells at 1, 3, and 5 hr, respectively. In vivo studies revealed that the tumor uptake in HSV-tk-expressing cells was 2.3-fold ( p < .001), 3.0-fold ( p < .001), and 5.5-fold ( p < .001) higher than the control cells at 1, 2, and 5 hr, respectively. FMAU was found to be more sensitive compared to our earlier studies using 9-[(3-18F-fluoro-1-hydroxy-2-propoxy)methyl]-guanine ([18F]-FHPG) and 9-(4-[18F]-fluoro-3-hydroxy-methylbutyl)guanine ([18F]-FHBG) in the same cell lines, although, the specificity was less than FHBG. These results suggest that while FMAU labeled with PET isotopes may be useful for imaging HSV-tk-expressing tumors in vivo, multitracer studies across additional tumor models are necessary in order to identify an optimal PET radiotracer.
Molecular–Genetic Imaging: A Nuclear Medicine–Based Perspective
Authors: Blasberg Ronald G. , Tjuvajev Juri Gelovani
Published: March 2018

Molecular imaging is a relatively new discipline, which developed over the past decade, initially driven by in situ reporter imaging technology. Noninvasive in vivo molecular–genetic imaging developed more recently and is based on nuclear (positron emission tomography [PET], gamma camera, autoradiography) imaging as well as magnetic resonance (MR) and in vivo optical imaging. Molecular–genetic imaging has its roots in both molecular biology and cell biology, as well as in new imaging technologies. The focus of this presentation will be nuclear-based molecular–genetic imaging, but it will comment on the value and utility of combining different imaging modalities. Nuclear-based molecular imaging can be viewed in terms of three different imaging strategies: (1) “indirect” reporter gene imaging; (2) “direct” imaging of endogenous molecules; or (3) “surrogate” or “bio-marker” imaging. Examples of each imaging strategy will be presented and discussed. The rapid growth of in vivo molecular imaging is due to the established base of in vivo imaging technologies, the established programs in molecular and cell biology, and the convergence of these disciplines. The development of versatile and sensitive assays that do not require tissue samples will be of considerable value for monitoring molecular–genetic and cellular processes in animal models of human disease, as well as for studies in human subjects in the future. Noninvasive imaging of molecular–genetic and cellular processes will complement established ex vivo molecular–biological assays that require tissue sampling, and will provide a spatial as well as a temporal dimension to our understanding of various diseases and disease processes.
IRDye78 Conjugates for Near-Infrared Fluorescence Imaging
Authors: Zaheer Atif , Wheat Thomas E. , Frangioni John V.
Published: March 2018

The detection of human malignancies by near-infrared (NIR) fluorescence will require the conjugation of cancer-specific ligands to NIR fluorophores that have optimal photoproperties and pharmacokinetics. IRDye78, a tetra-sulfonated heptamethine indocyanine NIR fluorophore, meets most of the criteria for an in vivo imaging agent, and is available as an N-hydroxysuccinimide ester for conjugation to low-molecular-weight ligands. However, IRDye78 has a high charge-to-mass ratio, complicating purification of conjugates. It also has a potentially labile linkage between fluorophore and ligand. We have developed an ion-pairing purification strategy for IRDye78 that can be performed with a standard C18 column under neutral conditions, thus preserving the stability of fluorophore, ligand, and conjugate. By employing parallel evaporative light scatter and absorbance detectors, all reactants and products are identified, and conjugate purity is maximized. We describe reversible and irreversible conversions of IRDye78 that can occur during sample purification, and describe methods for preserving conjugate stability. Using seven ligands, spanning several classes of small molecules and peptides (neutral, charged, and/or hydrophobic), we illustrate the robustness of these methods, and confirm that IRDye78 conjugates so purified retain bioactivity and permit NIR fluorescence imaging of specific targets.
Micro-MRI at 11.7 T of a Murine Brain Tumor Model Using Delayed Contrast Enhancement
Authors: Moats Rex A. , Velan-Mullan Sendhil , Jacobs Russell , Gonzalez-Gomez Ignacio , Dubowitz David J. , Taga Takashi , Khankaldyyan Vazgen , Schultz Linda , Fraser Scott , Nelson Marvin D. , Laug Walter E.
Published: March 2018

In vivo imaging methodologies allow for serial measurement of tumor size, circumventing the need for sacrificing mice at given time points. In orthotopically transplanted murine models of brain tumors, cross-section micro-MRI allows for visualization and measurement of the physically inaccessible tumors. To allow for long resident times of a contrast agent in the tumor, intraperitoneal administration was used as a route of injection for contrast-enhanced micro-MRI, and a simple method for relative tumor volume measurements was examined. A strategy for visualizing the variability of the delayed tumor enhancement was developed. These strategies were applied to monitor the growth of brain tumors xenotransplanted into nude mice and either treated with the antiangiogenic peptide EMD 121974 or an inactive control peptide. Each mouse was used as its own control. Serial imaging was done weekly, beginning at Day 7 after tumor cell implantation and continued for 7 weeks. Images obtained were reconstructed on the MRI instrument. The image files were transferred off line to be postprocessed to assess tumor growth (volume) and variability in enhancement (three-dimensional [3-D] intensity models). In a small study, tumor growth and response to treatment were followed using this methodology and the high-resolution images displayed in 3-D allowed for straightforward qualitative assessment of variable enhancement related to vascular factors and tumor age.
AMIDE: A Free Software Tool for Multimodality Medical Image Analysis
Authors: Loening Andreas Markus , Gambhir Sanjiv Sam
Published: March 2018

Amide's a Medical Image Data Examiner (AMIDE) has been developed as a user-friendly, open-source software tool for displaying and analyzing multimodality volumetric medical images. Central to the package's abilities to simultaneously display multiple data sets (e.g., PET, CT, MRI) and regions of interest is the on-demand data reslicing implemented within the program. Data sets can be freely shifted, rotated, viewed, and analyzed with the program automatically handling interpolation as needed from the original data. Validation has been performed by comparing the output of AMIDE with that of several existing software packages. AMIDE runs on UNIX, Macintosh OS X, and Microsoft Windows platforms, and it is freely available with source code under the terms of the GNU General Public License.
Functional Imaging of Proteolysis: Stromal and Inflammatory Cells Increase Tumor Proteolysis
Authors: Sameni Mansoureh , Dosescu Julie , Moin Kamiar , Sloane Bonnie F.
Published: March 2018

The underlying basement membrane is degraded during progression of breast and colon carcinoma. Thus, we imaged degradation of a quenched fluorescent derivative of basement membrane type IV collagen (DQ-collagen IV) by living human breast and colon tumor spheroids. Proteolysis of DQ-collagen IV by HCT 116 and HKh-2 human colon tumor spheroids was both intracellular and pericellular. In contrast, proteolysis of DQ-collagen IV by BT20 human breast tumor spheroids was pericellular. As stromal elements can contribute to proteolytic activities associated with tumors, we also examined degradation of DQ-collagen IV by human monocytes/macrophages and colon and breast fibroblasts. Fibroblasts themselves exhibited a modest amount of pericellular degradation. Degradation was increased 4–17-fold in cocultures of fibroblasts and tumor cells as compared to either cell type alone. Inhibitors of matrix metalloproteinases, plasmin, and the cysteine protease, cathepsin B, all reduced degradation in the cocultures. Monocytes did not degrade DQ-collagen IV; however, macrophages degraded DQ-collagen IV intracellularly. In coculture of tumor cells, fibroblasts, and macrophages, degradation of DQ-collagen IV was further increased. Imaging of living tumor and stromal cells has, thus, allowed us to establish that tumor proteolysis occurs pericellularly and intracellularly and that tumor, stromal, and inflammatory cells all contribute to degradative processes.