bluuebunny/crossref_metadata_2025 huggingface dataset:
Retinal Vessel Density in Optical Coherence Tomography Angiography in Optic Atrophy after Nonarteritic Anterior Ischemic Optic Neuropathy
Authors: Liu Chun-Hsiu , Kao Ling-Yuh , Sun Ming-Hui , Wu Wei-Chi , Chen Henry Shen-Lih
Published: February 2017

Aims. To compare optical coherence tomography angiography (OCT-A) retinal vasculature measurements between normal and optic atrophy after nonarteritic anterior ischemic optic neuropathy (NAION) subjects. Design. This prospective observational study was conducted between July 2015 and August 2016 at the ophthalmology outpatient department of a referral center in Taiwan. Peripapillary (4.5 × 4.5 mm) and parafoveal (6 × 6 mm) OCT-A scans were acquired. Measurements of the peripapillary region were obtained in two areas: (1) circumpapillary vessel density (cpVD) and (2) whole enface image vessel density (wiVD). Results. 13 participants with optic atrophy after NAION had lower peripapillary vessel density than the 18 age-matched participants in the healthy control (HC) group (p<0.001 for both cpVD and wiVD). However, the parafoveal vessel density was not significantly different between the two groups (p=0.49). The areas under the receiver operating characteristic curve for the HC and NAION eyes were 0.992 for cpVD and 0.970 for wiVD. cpVD and wiVD were significantly correlated with the average retinal nerve fiber layer thickness (p<0.001 for both). Conclusion. Peripapillary retinal perfusion is significantly decreased in optic atrophy after NAION. OCT-A may aid in the understanding of structure-function-perfusion relationships in NAION.
Compact Liquid Crystal Based Tunable Band-Stop Filter with an Ultra-Wide Stopband by Using Wave Interference Technique
Authors: Cai Longzhu , Xu Huan , Chu Daping
Published: February 2017

A wave interference filtering section that consists of three stubs of different lengths, each with an individual stopband of its own central frequency, is reported here for the design of band-stop filters (BSFs) with ultra-wide and sharp stopbands as well as large attenuation characteristics. The superposition of the individual stopbands provides the coverage over an ultra-wide frequency range. Equations and guidelines are presented for the application of a new wave interference technique to adjust the rejection level and width of its stopband. Based on that, an electrically tunable ultra-wide stopband BSF using a liquid crystal (LC) material for ultra-wideband (UWB) applications is designed. Careful treatment of the bent stubs, including impedance matching of the main microstrip line and bent stubs together with that of the SMA connectors and impedance adaptors, was carried out for the compactness and minimum insertion and reflection losses. The experimental results of the fabricated device agree very well with that of the simulation. The centre rejection frequency as measured can be tuned between 4.434 and 4.814 GHz when a biased voltage of 0–20 Vrms is used. The 3 dB and 25 dB stopband bandwidths were 4.86 GHz and 2.51 GHz, respectively, which are larger than that of other recently reported LC based tunable BSFs.
Neutrophils and Immunity: From Bactericidal Action to Being Conquered
Authors: Teng Tie-Shan , Ji Ai-ling , Ji Xin-Ying , Li Yan-Zhang
Published: February 2017

The neutrophil is the major phagocyte and the final effector cell of the innate immunity, with a primary role in the clearance of extracellular pathogens. Using the broad array of cytokines, extracellular traps, and effector molecules as the humoral arm, neutrophils play a crucial role in the host defense against pathogen infections. On the other hand, the pathogen has the capacity to overcome neutrophil-mediated host defense to establish infection causing human disease. Pathogens, such asS. aureus, have the potential to thwart neutrophil chemotaxis and phagocytosis and thereby succeed in evading killing by neutrophils. Furthermore,S. aureussurviving within neutrophils promotes neutrophil cytolysis, resulting in the release of host-derived molecules that promote local inflammation. Here, we provide a detailed overview of the mechanisms by which neutrophils kill the extracellular pathogens and how pathogens evade neutrophils degradation. This review will provide insights that might be useful for the development of novel therapies against infections caused by antibiotic resistant pathogens.
Estimation of Crash Severity on Mountainous Freeways in Chongqing
Authors: Meng Yunwei
Published: February 2017

Mountainous freeways always suffer from accidents due to special terrain, weather conditions, driving environment, and so on. Based on the records of 898 accidents that occurred on mountainous freeways in Chongqing during the past 6 years, the partial proportional odds model is used to identify the factors affecting the accident severity. The time of the accident, season, involvement of trucks, accident characteristics, speeding, maximum driving experience of involved drivers, and weather and road conditions are found to be important for the levels of accident severity. Zero to 6 a.m. and 19 to 24 p.m. are the times prone to serious traffic accidents. The probability of serious traffic accidents in summer and autumn is greater than that in spring and winter. Once a truck is involved in an accident, the consequence is often more severe. Turnover and speeding will result in a grave accident. When there is an experienced driver, the probability of serious traffic accidents is low. The fog is extremely unfavorable weather conditions. The probability of serious accident happening in the downgrade, ramp, curve, bridge, and tunnel sections is greater than the others. The results aim to provide valuable reference for traffic safety on mountainous freeways.
Serum Cytokine Levels and Their Relation to Clinical Features in Patients with Autoimmune Liver Diseases
Authors: Akberova Dilyara , Kiassov Andrei P. , Abdulganieva Diana
Published: February 2017

Serum cytokine levels were explored in a combined group of patients with autoimmune liver diseases (AILDs) and separately in patients with autoimmune hepatitis (AIH) and overlap syndrome. Overall, 60 patients with AILD, among them 32 patients with AIH and 28 patients with overlap syndrome, were included in the cross-sectional study. Serum cytokine levels were measured at baseline and compared to those of 21 healthy controls. Patients with AILD had significantly higher levels of IL-6 (0.70 (range 0.17–99.86) in patients with AILD compared to 0.40 (range 0.14–2.65) in controls,p<0.01), IL-8 (1.66 (0.45–34.58) versus 0.53 (0.35–2.38), resp.,p<0.01), and TNF-α(2.61 (0.23–120.88) versus 1.65 (0.21–7.54), resp.,p<0.01). Adjusted logistic regression analysis revealed a pronounced relation of IL-8 and AILD, 48.36 (3.63–643.60), as well as AIH, 18.54 (1.08–318.54), and overlap syndrome, 23.85 (2.37–240.23), while the associations between the level of other cytokines and AILD were assessed as nonsignificant. In the language of absolute numbers, the increase of IL-8 serum level by 1 pg/mL had increased the chance for a patient to find himself in a group of AILD by 48.36 times. Also, high IL-8 serum levels were strongly related to clinical parameters.
Adrenomedullin RegulatesIL-1βGene Expression in F4/80+ Macrophages during Synovial Inflammation
Authors: Takano Shotaro , Uchida Kentaro , Miyagi Masayuki , Inoue Gen , Aikawa Jun , Iwabuchi Kazuya , Takaso Masashi
Published: February 2017

Adrenomedullin (AM) plays an important role in the regulation of inflammatory processes; however, the role and expression of AM in synovial inflammation have not been determined. To investigate the expression and role of AM in inflamed synovial tissue (ST), the gene expression profiles of AM in the ST, including synovial macrophages and fibroblasts, of a murine patellar surgical dislocation model were characterized. In addition, the effects of interleukin-(IL-) 1βand AM in cultured synovial cells were also examined. CD11c+macrophages were found to be elevated in ST of the surgically dislocated patella. Higher gene expression ofCD11c,IL-1β,AM, receptor activity-modifying proteins 2(RAMP2), and 3(RAMP3)was also observed in ST obtained from the dislocated side.AMexpression was also significantly increased in synovial fibroblasts and macrophages in response to IL-1βtreatment. Synovial macrophages also highly expressedRAMP3compared to fibroblasts and this expression was further stimulated by exogenously added IL-1β. Further, the treatment of the F4/80-positive cell fraction obtained from ST with AM inhibitedIL-1βexpression. Taken together, these findings demonstrated that AM was produced by synovial fibroblasts and macrophages in inflamed ST and that increased levels of AM may exert anti-inflammatory effects on synovial macrophages.
Long-Term Oncological Outcomes for Young Men Undergoing Radical Prostatectomy for Localized Prostate Cancer
Authors: Milonas Daimantas , Venclovas Zilvinas , Gudinaviciene Inga , Zviniene Kristina , Matjosaitis Aivaras Jonas
Published: February 2017

Aim. The aim of this study was to describe PCa characteristics and long-term outcomes in young men aged ≤55 years after radical prostatectomy (RP) and to compare them with older men cohort.Methods. Among 2,200 patients who underwent RP for clinically localized PCa at our centre between 2001 and 2015, 277 (10.3%) men aged ≤55 years were identified. All preoperative and pathological parameters were compared between groups. Biochemical progression free survival (BPFS) and disease progression free survival (DPFS) were assessed at 5 and 10 years.Results. Men aged ≤55 years had similar pathological tumor characteristics and biochemical recurrence rate (BCR) compared to their older counterparts. Disease progression rate 2.5% versus 0.4% was higher in older patients (p=0.026). BPFS rate was not different in both study groups. Estimated 10-year DPFS was 98.8% in younger men compared to 89.2% in their older counterparts (p=0.031). Multivariate Cox regression showed that Gleason score lymph-nodes and surgical margins status were significant predictors for disease progression.Conclusions. In our cohort, men aged ≤55 years had similar pathological PCa characteristics and BCR rate in comparison with older men. RP can be performed with excellent long-term DPFS results in men with localized PCa at ≤55 years of age.
Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone
Authors: Rathkopf Dana E. , Antonarakis Emmanuel S. , Shore Neal D. , Tutrone Ronald F. , Alumkal Joshi J. , Ryan Charles J. , Saleh Mansoor , Hauke Ralph J. , Bandekar Rajesh , Maneval Edna Chow , de Boer Carla J. , Yu Margaret K. , Scher Howard I.
Published: February 2017

Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC).

Experimental Design: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment.

Results: Forty-six patients enrolled in the AAP-naïve (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months–not reached) and 3.7 months (95% CI, 2.8–5.6 months), and median time on treatment 21 months (range, 2.6–37.5) and 4.9 months (range, 1.3–23.2), for the AAP-naïve and post-AAP cohorts, respectively. Eighty percent (95% CI, 59–93) and 64% (95% CI, 43–82) of AAP-naïve and 43% (95% CI, 22–66) and 10% (95% CI, 1–30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain.

Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naïve and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544–51. ©2017 AACR.
Hypoxia Selectively Enhances Integrin α5β1 Receptor Expression in Breast Cancer to Promote Metastasis
Authors: Ju Julia A. , Godet Inês , Ye I Chae , Byun Jungmin , Jayatilaka Hasini , Lee Sun Joo , Xiang Lisha , Samanta Debangshu , Lee Meng Horng , Wu Pei-Hsun , Wirtz Denis , Semenza Gregg L. , Gilkes Daniele M.
Published: February 2017

Metastasis is the leading cause of breast cancer mortality. Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix (ECM) in the metastatic process. Therefore, the contribution of potential ECM-binding receptors in this process was explored. Using a bioinformatics approach, the expression of all integrin receptor subunits, in two independent breast cancer patient datasets, were analyzed to determine whether integrin status correlates with a validated hypoxia-inducible gene signature. Subsequently, a large panel of breast cancer cell lines was used to validate that hypoxia induces the expression of integrins that bind to collagen (ITGA1, ITGA11, ITGB1) and fibronectin (ITGA5, ITGB1). Hypoxia-inducible factors (HIF-1 and HIF-2) are directly required for ITGA5 induction under hypoxic conditions, which leads to enhanced migration and invasion of single cells within a multicellular 3D tumor spheroid but did not affect migration in a 2D microenvironment. ITGB1 expression requires HIF-1α, but not HIF-2α, for hypoxic induction in breast cancer cells. ITGA5 (α5 subunit) is required for metastasis to lymph nodes and lungs in breast cancer models, and high ITGA5 expression in clinical biopsies is associated with an increased risk of mortality.

Implications: These results reveal that targeting ITGA5 using inhibitors that are currently under consideration in clinical trials may be beneficial for patients with hypoxic tumors. Mol Cancer Res; 15(6); 723–34. ©2017 AACR.
OTX2 Activity at Distal Regulatory Elements Shapes the Chromatin Landscape of Group 3 Medulloblastoma
Authors: Boulay Gaylor , Awad Mary E. , Riggi Nicolo , Archer Tenley C. , Iyer Sowmya , Boonseng Wannaporn E. , Rossetti Nikki E. , Naigles Beverly , Rengarajan Shruthi , Volorio Angela , Kim James C. , Mesirov Jill P. , Tamayo Pablo , Pomeroy Scott L. , Aryee Martin J. , Rivera Miguel N.
Published: February 2017

Medulloblastoma is the most frequent malignant pediatric brain tumor and is divided into at least four subgroups known as WNT, SHH, Group 3, and Group 4. Here, we characterized gene regulation mechanisms in the most aggressive subtype, Group 3 tumors, through genome-wide chromatin and expression profiling. Our results show that most active distal sites in these tumors are occupied by the transcription factor OTX2. Highly active OTX2-bound enhancers are often arranged as clusters of adjacent peaks and are also bound by the transcription factor NEUROD1. These sites are responsive to OTX2 and NEUROD1 knockdown and could also be generated de novo upon ectopic OTX2 expression in primary cells, showing that OTX2 cooperates with NEUROD1 and plays a major role in maintaining and possibly establishing regulatory elements as a pioneer factor. Among OTX2 target genes, we identified the kinase NEK2, whose knockdown and pharmacologic inhibition decreased cell viability. Our studies thus show that OTX2 controls the regulatory landscape of Group 3 medulloblastoma through cooperative activity at enhancer elements and contributes to the expression of critical target genes.

Significance: The gene regulation mechanisms that drive medulloblastoma are not well understood. Using chromatin profiling, we find that the transcription factor OTX2 acts as a pioneer factor and, in cooperation with NEUROD1, controls the Group 3 medulloblastoma active enhancer landscape. OTX2 itself or its target genes, including the mitotic kinase NEK2, represent attractive targets for future therapies. Cancer Discov; 7(3); 288–301. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 235
Role of Apamin-Sensitive Calcium-Activated Small-Conductance Potassium Currents on the Mechanisms of Ventricular Fibrillation in Pacing-Induced Failing Rabbit Hearts
Authors: Yin Dechun , Hsieh Yu-Cheng , Tsai Wei-Chung , Zhi-Yang Wu Adonis , Jiang Zhaolei , Chan Yi-Hsin , Xu Dongzhu , Yang Na , Shen Changyu , Chen Zhenhui , Lin Shien-Fong , Chen Peng-Sheng , Everett Thomas H.
Published: February 2017

Background—

Ventricular fibrillation (VF) during heart failure is characterized by stable reentrant spiral waves (rotors). Apamin-sensitive small-conductance calcium-activated potassium currents (
I
KAS
) are heterogeneously upregulated in failing hearts. We hypothesized that
I
KAS
influences the location and stability of rotors during VF.

Methods and Results—

Optical mapping was performed on 9 rabbit hearts with pacing-induced heart failure. The epicardial right ventricular and left ventricular surfaces were simultaneously mapped in a Langendorff preparation. At baseline and after apamin (100 nmol/L) infusion, the action potential duration (APD
80
) was determined, and VF was induced. Areas with a >50% increase in the maximum action potential duration (ΔAPD) after apamin infusion were considered to have a high
I
KAS
distribution. At baseline, the distribution density of phase singularities during VF in high
I
KAS
distribution areas was higher than in other areas (0.0035±0.0011 versus 0.0014±0.0010 phase singularities/pixel;
P
=0.004). In addition, high dominant frequencies also colocalized to high
I
KAS
distribution areas (26.0 versus 17.9 Hz;
P
=0.003). These correlations were eliminated during VF after apamin infusion, as the number of phase singularities (17.2 versus 11.0;
P
=0.009) and dominant frequencies (22.1 versus 16.2 Hz;
P
=0.022) were all significantly decreased. In addition, reentrant spiral waves became unstable after apamin infusion, and the duration of VF decreased.

Conclusions—

The
I
KAS
current influences the mechanism of VF in failing hearts as phase singularities, high dominant frequencies, and reentrant spiral waves all correlated to areas of high
I
KAS
. Apamin eliminated this relationship and reduced VF vulnerability.
Effect of Sleep-Disordered Breathing on Appropriate Implantable Cardioverter-Defibrillator Therapy in Patients With Heart Failure
Authors: Kwon Younghoon , Koene Ryan J. , Kwon Osung , Kealhofer Jessica V. , Adabag Selcuk , Duval Sue
Published: February 2017

Background—

Patients with heart failure and reduced ejection fraction are at increased risk of malignant ventricular arrhythmias. Implantable cardioverter-defibrillator (ICD) is recommended to prevent sudden cardiac death in some of these patients. Sleep-disordered breathing (SDB) is highly prevalent in this population and may impact arrhythmogenicity. We performed a systematic review and meta-analysis of prospective studies that assessed the impact of SDB on ICD therapy.

Methods and Results—

Relevant prospective studies were identified in the Ovid MEDLINE, EMBASE, and Google Scholar databases. Weighted risk ratios of the association between SDB and appropriate ICD therapies were estimated using random effects meta-analysis. Nine prospective cohort studies (n=1274) were included in this analysis. SDB was present in 52% of the participants. SDB was associated with a 55% higher risk of appropriate ICD therapies (45% versus 28%; risk ratio, 1.55; 95% confidence interval, 1.32–1.83). In a subgroup analysis based on the subtypes of SDB, the risk was higher in both central (risk ratio, 1.50; 95% confidence interval, 1.11–2.02) and obstructive (risk ratio, 1.43; 95% confidence interval, 1.01–2.03) sleep apnea.

Conclusions—

SDB is associated with an increased risk of appropriate ICD therapy in patients with heart failure and reduced ejection fraction.
Familial Occurrence of Atrioventricular Nodal Reentrant Tachycardia
Authors: Michowitz Yoav , Anis-Heusler Adi , Reinstein Eyal , Tovia-Brodie Oholi , Glick Aharon , Belhassen Bernard
Published: February 2017

Background—

Atrioventricular nodal reentrant tachycardia (AVNRT) is considered a sporadic disease occurring in ≈22.5 cases per 10 000 in the general population. We define the prevalence and characteristics of familial AVNRT among patients who underwent radiofrequency ablation.

Methods and Results—

Ablation reports of all patients with familial AVNRT (at least 2 first-degree family members) who underwent radiofrequency ablation in our institution and in another hospital were reviewed. There were 1587 patients from our institution, of whom 20 had ≥1 first-degree relatives with AVNRT. This indicates a familial AVNRT prevalence of 127 cases per 10 000 (95% confidence interval, 82–196/10 000). First-degree relatives of patients with AVNRT presented a hazard ratio of at least 3.6 for exhibiting AVNRT compared with the general population. After inclusion of 4 families with familial AVNRT who underwent ablation at another hospital our population study comprised a total of 24 families (50 patients) with AVNRT. Patients at ablation were younger in the familial AVNRT group when compared with the sporadic AVNRT group (44.2±19 versus 54.8±18 years old,
P
=0.0001). The male/female ratio was similar, with female predominance. The supraventricular tachycardia mechanism was typical slow/fast reentry in most cases in both groups. The most common familial relationship in our 24 families included a parent and a child in 67% of cases and less often 2 siblings (29%).

Conclusions—

Familial AVNRT prevalence is higher than previously believed suggesting that this arrhythmia may have a genetic component. Autosomal dominance with incomplete penetrance is the most likely mode of inheritance.
Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies
Authors: Hedman Åsa K. , Mendelson Michael M. , Marioni Riccardo E. , Gustafsson Stefan , Joehanes Roby , Irvin Marguerite R. , Zhi Degui , Sandling Johanna K. , Yao Chen , Liu Chunyu , Liang Liming , Huan Tianxiao , McRae Allan F. , Demissie Serkalem , Shah Sonia , Starr John M. , Cupples L. Adrienne , Deloukas Panos , Spector Timothy D. , Sundström Johan , Krauss Ronald M. , Arnett Donna K. , Deary Ian J. , Lind Lars , Levy Daniel , Ingelsson Erik
Published: February 2017

Background—

Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications.

Methods and Results—

To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine–guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (
P
<1.08E-07) and replicated 33 (at Bonferroni-corrected
P
<0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglycerides and high-density lipoprotein cholesterol (HDL-C; cg27243685;
P
=8.1E-26 and 9.3E-19) was associated with
cis
-expression of a reverse cholesterol transporter (
ABCG1; P
=7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15–1.66;
P
=0.0007). We found significant
cis
-methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels (
P
TC
=0.004,
P
HDL-C
=0.008 and
P
triglycerides
=0.00003) and coronary heart disease (
P
=0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at
APOB
were
cis
-methylation quantitative trait loci for a low-density lipoprotein cholesterol–related differentially methylated locus.

Conclusions—

We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events.
Detection and Monitoring of Acute Myocarditis Applying Quantitative Cardiovascular Magnetic Resonance
Authors: von Knobelsdorff-Brenkenhoff Florian , Schüler Johannes , Dogangüzel Serkan , Dieringer Matthias A. , Rudolph Andre , Greiser Andreas , Kellman Peter , Schulz-Menger Jeanette
Published: February 2017

Background—

Cardiovascular magnetic resonance based on the Lake Louise Criteria is used to make the diagnosis of acute myocarditis. Novel quantitative parametric mapping techniques promise to overcome some of its limitations. We aimed to evaluate quantitative cardiovascular magnetic resonance to detect and monitor acute myocarditis.

Methods and Results—

Eighteen patients with clinical diagnosis of acute myocarditis (25 years [23–38 years]; 78% males) were prospectively enrolled and repeatedly underwent cardiovascular magnetic resonance at 1.5 T seven days (5–10 days) after symptom onset (FU0), after 5 weeks (FU1), and after 6 months (FU2). Eighteen age- and sex-matched healthy subjects served as controls. Cardiovascular magnetic resonance included imaging of edema, hyperemia, necrosis, and fibrosis using semiquantitative T2-weighted spin echo, T2 mapping, and T1 mapping before and 3 and 10 minutes after gadobutrol administration. Extracellular volume for diffuse and late gadolinium enhancement for focal fibrosis were assessed. Compared with controls, patients had significantly higher global T2 times at FU0 (55.1 ms [53.3–57.2 ms] versus 50.2 ms [49.2–52.0 ms];
P
<0.001) and at FU1 (52.0 ms [52.0–53.2 ms];
P
=0.007), which normalized at FU2 (50.9 ms [49.6–53.3 ms];
P
=0.323). Global native T1 times in patients were elevated acutely (1004 ms [988–1048 ms] versus 975 ms [957–1004 ms];
P
=0.002) and remained elevated throughout the follow-up (FU1: 998 ms [990–1027 ms];
P
=0.014; FU2: 1000 ms [972–1027 ms];
P
=0.044). Global extracellular volume fraction was statistically not different between patients and controls (
P
=0.057). 77.8% (14/18) of patients had focal late gadolinium enhancement. T2 ratio was significantly elevated in patients with myocarditis at FU0 (2.2 [2.0–2.3] versus 1.6 [1.5–1.7];
P
<0.001). The difference decreased during follow-up (FU1: 1.9 [1.7–1.9];
P
=0.001 and FU2: 1.7 [1.7–1.8];
P
=0.053). The diagnostic accuracy to discriminate between patients with acute myocarditis and healthy controls was 86% for T2>52 ms, 78% for native T1>981 ms, 74% for extracellular volume fraction >0.24, and 100% for T2 ratio >1.9.

Conclusions—

Although both T2 and T1 mapping reliably detected acute myocarditis, only T2 mapping discriminated between acute and healed stages, underlining the incremental value of T2 mapping.
Optimal Adenosine Stress for Maximum Stress Perfusion, Coronary Flow Reserve, and Pixel Distribution of Coronary Flow Capacity by Kolmogorov–Smirnov Analysis
Authors: Kitkungvan Danai , Lai Dejian , Zhu Hongjian , Roby Amanda E. , Johnson Nils P. , Steptoe Derek D. , Patel Monica B. , Kirkeeide Richard , Gould K. Lance
Published: February 2017

Background—

Different adenosine stress imaging protocols have not been systemically validated for absolute myocardial perfusion and coronary flow reserve (CFR) by positron emission tomography, where submaximal stress precludes assessing physiological severity of coronary artery disease.

Methods and Results—

In 127 volunteers, serial rest–stress positron emission tomography scans using rubidium-82 with various adenosine infusion protocols identified (1) the protocol with maximum stress perfusion and CFR, (2) test–retest precision in same subject, (3) stress perfusion and CFR after adenosine compared with dipyridamole, (4) heterogeneity of coronary flow capacity combining stress perfusion and CFR, and (5) potential relevance for patients with risk factors or coronary artery disease. The adenosine 6-minute infusion with rubidium-82 injection at 3 minutes caused CFR that was significantly 15.7% higher than the 4-minute adenosine infusion with rubidium-82 injection at 2 minutes and significantly more homogeneous by Kolmogorov–Smirnov analysis for histograms of 1344 pixel range of perfusion in paired positron emission tomographies. In a coronary artery disease cohort separate from volunteers of this study, compared with the 3/6-minute protocol, the 2/4-minute adenosine protocol would potentially have changed 332 of 1732 (19%) positron emission tomographies at low-risk physiological severity CFR ≥2.3 to CFR <2.0, thereby implying high-risk quantitative severity potentially appropriate for interventions but because of suboptimal stress of the 2/4 protocol in some patients.

Conclusions—

The 6-minute adenosine infusion with rubidium-82 activation at 3 minutes produced CFR that averaged 15.7% higher than that in the 2/4-minute protocol, thereby potentially providing essential information for personalized management in some patients.
Interventional Treatment of Pulmonary Embolism
Authors: Dudzinski David M. , Giri Jay , Rosenfield Kenneth
Published: February 2017

Pulmonary embolism (PE) is a serious and prevalent cause of vascular disease. Nevertheless, optimal treatment for many phenotypes of PE remains uncertain. Treating PE requires appropriate risk stratification as a first step. For the highest-risk PE, presenting as shock or arrest, emergent systemic thrombolysis or embolectomy is reasonable, while for low-risk PE, anticoagulation alone is often chosen. Normotensive patients with PE but with indicia of right heart dysfunction (by biomarkers or imaging) constitute an intermediate-risk group for whom there is controversy on therapeutic strategy. Some intermediate-risk patients with PE may require urgent stabilization, and ≈10% will decompensate hemodynamically and suffer high mortality, though identifying these specific patients remains challenging. Systemic thrombolysis is a consideration, but its risks of major and intracranial hemorrhages rival overall harms from intermediate PE. Multiple hybrid pharmacomechanical approaches have been devised to capture the benefits of thrombolysis while reducing its risks, but there is limited aggregate clinical experience with such novel interventional strategies. One method to counteract uncertainty and generate a consensus multidisciplinary prognostic and therapeutic plan is through a Pulmonary Embolism Response Team, which combines expertise from interventional cardiology, interventional radiology, cardiac surgery, cardiac imaging, and critical care. Such a team can help determine which intervention—catheter-directed fibrinolysis, ultrasound-assisted thrombolysis, percutaneous mechanical thrombus fragmentation, or percutaneous or surgical embolectomy—is best suited to a particular patient. This article reviews these various modalities and the background for each.
Soluble ST2 in Heart Failure With Preserved Ejection Fraction
Authors: AbouEzzeddine Omar F. , McKie Paul M. , Dunlay Shannon M. , Stevens Susanna R. , Felker G. Michael , Borlaug Barry A. , Chen Horng H. , Tracy Russell P. , Braunwald Eugene , Redfield Margaret M.
Published: February 2017

Background

Soluble ST2 is a biomarker that is elevated in certain systemic inflammatory diseases. Comorbidity‐driven microvascular inflammation is postulated to play a key role in heart failure with preserved ejection fraction (
HF
p
EF
) pathophysiology, but data on how
sST
2 relates to clinical characteristics or inflammatory conditions or biomarkers in
HF
p
EF
are limited. We sought to determine circulating levels and clinical correlates of
sST
2 in
HF
pEF.

Methods and Results

At enrollment, patients (n=174) from the Phosphodiesterase‐5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial of sildenafil in
HF
p
EF
had
sST
2 levels measured. Clinical characteristics; cardiac structure and function; exercise performance; and biomarkers of neurohumoral activation, systemic inflammation and fibrosis, and myocardial necrosis were assessed in relation to
sST
2 levels. Median
sST
2 levels in male and female HFpEF patients were 36.7 ng/mL (range 30.9–49.2 ng/mL; reference range 4–31 ng/mL) and 30.8 ng/mL (range 25.3–39.3 ng/mL; reference range 2–21 ng/mL), respectively. Among
HF
p
EF
patients, higher
sST
2 levels were associated with the presence of diabetes mellitus; atrial fibrillation; renal dysfunction; right ventricular pressure overload and dysfunction; systemic congestion; exercise intolerance; and biomarkers of systemic inflammation and fibrosis, neurohumoral activation, and myocardial necrosis (
P
<0.05 for all).
sST
2 was not associated with left ventricular structure or left ventricular systolic or diastolic function.

Conclusions

In
HF
p
EF
,
sST
2 levels were associated with proinflammatory comorbidities, right ventricular pressure overload and dysfunction, and systemic congestion but not with left ventricular geometry or function. These data suggest that sST2 may be a marker of systemic inflammation in
HF
p
EF
and potentially of extracardiac origin.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
00763867.
Evaluation of Timing and Route of Epinephrine in a Neonatal Model of Asphyxial Arrest
Authors: Vali Payam , Chandrasekharan Praveen , Rawat Munmun , Gugino Sylvia , Koenigsknecht Carmon , Helman Justin , Jusko William J. , Mathew Bobby , Berkelhamer Sara , Nair Jayasree , Wyckoff Myra H. , Lakshminrusimha Satyan
Published: February 2017

Background

Epinephrine administered by low umbilical venous catheter (
UVC
) or endotracheal tube (
ETT
) is indicated in neonates who fail to respond to positive pressure ventilation and chest compressions at birth. Pharmacokinetics of
ETT
epinephrine via fluid‐filled lungs or
UVC
epinephrine in the presence of fetal shunts is unknown. We hypothesized that epinephrine administered by
ETT
or low
UVC
results in plasma epinephrine concentrations and rates of return of spontaneous circulation (
ROSC
) similar to right atrial (
RA
) epinephrine.

Methods and Results

Forty‐four lambs were randomized into the following groups:
RA
epinephrine (0.03 mg/kg), low
UVC
epinephrine (0.03 mg/kg), postcompression
ETT
epinephrine (0.1 mg/kg), and precompression
ETT
epinephrine (0.1 mg/kg). Asystole was induced by umbilical cord occlusion. Resuscitation was initiated following 5 minutes of asystole. Thirty‐eight of 44 lambs achieved
ROSC
(10/11, 9/11, and 12/22 in the
RA
,
UVC
, and
ETT
groups, respectively; subsequent
RA
epinephrine resulted in a total
ROSC
of 19/22 in the
ETT
groups). Median time (interquartile range) to achieve
ROSC
was significantly longer in the
ETT
group (including those that received
RA
epinephrine) compared to the intravenous group (4.5 [2.9–7.4] versus 2 [1.9–3] minutes;
P
=0.02).
RA
and low
UVC
epinephrine administration achieved comparable peak plasma epinephrine concentrations (470±250 versus 450±190 ng/mL) by 1 minute compared to
ETT
values of 130±60 ng/mL at 5 minutes;
P
=0.03. Following
ROSC
with
ETT
epinephrine alone, there was a delayed peak epinephrine concentration (652±240 ng/mL).

Conclusions

The absorption of
ETT
epinephrine is low and delayed at birth.
RA
and low
UVC
epinephrine rapidly achieve high plasma concentrations resulting in
ROSC
.
Cost‐Effectiveness of Intensifying Lipid‐Lowering Therapy With Statins Based on Individual Absolute Benefit in Coronary Artery Disease Patients
Authors: Stam‐Slob Manon C. , van der Graaf Yolanda , Greving Jacoba P. , Dorresteijn Jannick A.N. , Visseren Frank L.J.
Published: February 2017

Background

A validated prediction model estimates the absolute benefit of intensive versus standard lipid‐lowering therapy (
LLT
) with statins on next major cardiovascular events for individual patients with coronary artery disease. We aimed to assess whether targeting intensive
LLT
therapy to
coronary artery disease
patients with the highest predicted absolute benefit is cost‐effective compared to treating all with standard or all with intensive
LLT
.

Methods and Results

A lifetime Markov model was constructed for
coronary artery disease
patients (n=10 000) with mean age 61 years. Number of
major cardiovascular events
, (non) vascular death, costs, and quality‐adjusted life years (
QALY
s) were estimated for the following strategies: (1) standard
LLT
for all (reference strategy); (2) intensive
LLT
for those with 5‐year absolute
major cardiovascular events
risk reduction (
ARR
) ≥3%, ≥2.3%, or ≥1.5% (corresponding to ≥20%, ≥15%, or ≥10% 5‐year
major cardiovascular events
risk); and (3) intensive
LLT
for all. With intensive
LLT
for those with ≥3% 5‐year
ARR
(13% of patients), 380
QALY
s were gained for €2423/
QALY
. Using a threshold of ≥2.3%
ARR
(26% of patients), 630
QALY
s were gained for €5653/
QALY
. Using a threshold of ≥1.5%
ARR
(56% of patients), 1020
QALY
s were gained for €10 960/
QALY
. By treating all intensively, 1410
QALY
s were gained (0.14
QALY
per patient) for €17 223/
QALY
. With benefit‐based treatment, 0.16 to 0.17
QALY
was gained per treated patient.

Conclusions

Intensive
LLT
with statins for all coronary artery disease patients results in the highest overall
QALY
gain against acceptable costs. However, the number of
QALY
s gained with intensive
LLT
by statins in individual patients can be increased with selective benefit‐based treatment.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifiers:
NCT
00327691 and
NCT
00159835
Pre‐Implantation Balloon Aortic Valvuloplasty and Clinical Outcomes Following Transcatheter Aortic Valve Implantation: A Propensity Score Analysis of the UK Registry
Authors: Martin Glen P. , Sperrin Matthew , Bagur Rodrigo , de Belder Mark A. , Buchan Iain , Gunning Mark , Ludman Peter F. , Mamas Mamas A.
Published: February 2017

Background

Aortic valve predilation with balloon aortic valvuloplasty (
BAV
) is recommended before transcatheter aortic valve implantation (
TAVI
), despite limited data around the requirement of this preprocedural step and the potential risks of embolization. This study aimed to investigate the trends in practice and associations of
BAV
on short‐term outcomes in the
UK TAVI
registry.

Methods and Results

Eleven clinical endpoints were investigated, including 30‐day mortality, myocardial infarction, aortic regurgitation, valve dysfunction, and composite early safety. All endpoints were defined as per the
VARC
‐2 definitions. Odd ratios of each endpoint were estimated using logistic regression, with data analyzed in balloon‐ and self‐expandable valve subgroups. Propensity scores were calculated using patient demographics and procedural variables, which were included in the models of each endpoint to adjust for measured confounding. Between 2007 and 2014, 5887 patients met the study inclusion criteria, 1421 (24.1%) of whom had no
BAV
before
TAVI
valve deployment. We observed heterogeneity in the use of
BAV
nationally, both temporally and by center experience; rates of
BAV
in pre‐
TAVI
workup varied between 30% and 97% across
TAVI
centers. All endpoints were similar between treatment groups in SAPIEN (Edwards Lifesciences Inc., Irvine, CA) valve patients. After correction for multiple testing, none of the endpoints in CoreValve (Medtronic, Minneapolis, MN) patients were significantly different between patients with or without predilation.

Conclusions

Performing
TAVI
without predilation was not associated with adverse short‐term outcomes post procedure, especially when using a balloon‐expandable prosthesis. Randomized trials including different valve types are required to provide conclusive evidence regarding the utility of predilation before‐
TAVI
.
Trends in Coronary Revascularization and Ischemic Heart Disease–Related Mortality in Israel
Authors: Blumenfeld Orit , Na'amnih Wasef , Shapira‐Daniels Ayelet , Lotan Chaim , Shohat Tamy , Shapira Oz M.
Published: February 2017

Background

We investigated national trends in volume and outcomes of percutaneous coronary angioplasty (
PCI
), coronary artery bypass grafting (
CABG
), and ischemic heart disease–related mortality in Israel.

Methods and Results

Using
International Classification of Diseases
9th and 10th revision codes, we linked 5 Israeli national databases, including the Israel Center for Disease Control National
PCI
and
CABG
Registries, the Ministry of Health Hospitalization Report, the Center of Bureau of Statistics, and the Ministry of Interior Mortality Report, to assess the annual
PCI
and
CABG
volume, procedural mortality, comorbidities, and ischemic heart disease‐related mortality between 2002 and 2014. Trends over time were analyzed using linear regression, assuming a Poisson distribution. A total of 298 390 revascularization procedures (
PCI
: 255 724,
CABG
: 42 666) were performed during the study period.
PCI
volume increased by 9% from 2002 to 2008 (387.4/100 000 to 423.2/100 000), steadily decreasing by 10.5% to 378.5/100 000 in 2014 (
P
=0.70 for the trend).
CABG
volume decreased by 59% (109.0/100 000 to 45.2/100 000) from 2002 to 2013, leveling at 46.4/100 000 (
P
<0.0001).
PCI
/
CABG
ratio increased from 3.6 in 2002 to 8.5 in 2013, slightly decreasing to 8.2 by 2014 (
P
<0.0001). In‐hospital procedural mortality remained stable (
PCI
: 1.2–1.6%,
P
=0.34,
CABG
: 3.7–4.4%,
P
=0.29) despite a significant change in patient clinical profile. During the course of the study, ischemic heart disease‐related mortality decreased by 46% (84.6–46/100 000,
P
<0.001).

Conclusions

We observed a dramatic change in coronary revascularization procedures type and volume, and a marked decrease in ischemic heart disease‐related mortality in Israel. The reasons for the observed changes remain unclear and need to be further investigated.
Impact of Expanding the Prehospital Stroke Bypass Time Window in a Large Geographic Region
Authors: Stiell Ian G. , Clement Catherine M. , Campbell Kristy , Sharma Mukul , Socha Doug , Sivilotti Marco L.A. , Jin Albert , Perry Jeffrey J. , Lumsden Jim , Martin Cally , Froats Mark , Dionne Richard , Trickett John
Published: February 2017

Background and Purpose—

The Ontario Acute Stroke Medical Redirect Paramedic Protocol (ASMRPP) was revised to allow paramedics to bypass to designated stroke centers if total transport time would be <2 hours and total time from symptom onset <3.5 hours. We sought to evaluate the impact and safety of implementing the Revised ASMRPP.

Methods—

We conducted a 12-month implementation study involving prehospital patients presenting with possible stroke symptoms. A total of 1317 basic and advanced life support paramedics, of 9 land services in 10 rural counties and 5 cities, used the Revised ASMRPP to take appropriate patients directly to 6 designated stroke centers.

Results—

We enrolled 1277 patients with 98.8% paramedic compliance in form completion. Of these, 755 (61.2%) met the redirect criteria and had these characteristics: mean age 72.1 (range 16–101), male 51.1%, mean time scene to hospital 16.7 minutes (range 0–92). Paramedics demonstrated excellent interobserver agreement (κ, 0.94; 95% confidence interval, 0.91–0.96) and 97.9% accuracy in interpretation of the Revised ASMRPP. Prehospital adverse events occurred in 14.7% of patients, but few were life-threatening. Overall, 71.4% of 755 cases had a stroke code activated at the hospital and 23.2% received thrombolysis. For the 189 potential stroke patients picked up in 1 city, the ASMRPP classified thrombolysis administration with sensitivity 100% and specificity 37.3% and a final diagnosis of stroke, with sensitivity 86.1% and specificity 41.9%.

Conclusions—

In a large urban–rural area with 9 paramedic services, we demonstrated accurate, safe, and effective implementation of the Revised ASMRPP. These revisions will allow more patients with stroke to benefit from early treatment.
Rivaroxaban Versus Dabigatran or Warfarin in Real-World Studies of Stroke Prevention in Atrial Fibrillation
Authors: Bai Ying , Deng Hai , Shantsila Alena , Lip Gregory Y.H.
Published: February 2017

Background and Purpose—

This study was designed to evaluate the effectiveness and safety of rivaroxaban in real-world practice compared with effectiveness and safety of dabigatran or warfarin for stroke prevention in atrial fibrillation through meta-analyzing observational studies.

Methods—

Seventeen studies were included after searching in PubMed for studies reporting the comparative effectiveness and safety of rivaroxaban versus dabigatran (n=3), rivaroxaban versus Warfarin (n=11), or both (n=3) for stroke prevention in atrial fibrillation.

Results—

Overall, the risks of stroke/systematic thromboembolism with rivaroxaban were similar when compared with those with dabigatran (stroke/thromboembolism: hazard ratio, 1.02; 95% confidence interval, 0.91–1.13; I
2
=70.2%, N=5), but were significantly reduced when compared with those with warfarin (hazard ratio, 0.75; 95% confidence interval, 0.64–0.85; I
2
=45.1%, N=9). Major bleeding risk was significantly higher with rivaroxaban than with dabigatran (hazard ratio, 1.38; 95% confidence interval, 1.27–1.49; I
2
=26.1%, N=5), but similar to that with warfarin (hazard ratio, 0.99; 95% confidence interval, 0.91–1.07; I
2
=0.0%, N=6). Rivaroxaban was associated with increased all-cause mortality and gastrointestinal bleeding, but similar risk of acute myocardial infarction and intracranial hemorrhage when compared with dabigatran. When compared with warfarin, rivaroxaban was associated with similar risk of any bleeding, mortality, and acute myocardial infarction, but a higher risk of gastrointestinal bleeding and lower risk of intracranial hemorrhage.

Conclusions—

In this systematic review and meta-analysis, rivaroxaban was as effective as dabigatran, but was more effective than warfarin for the prevention of stroke/thromboembolism in atrial fibrillation patients. Major bleeding risk was significantly higher with rivaroxaban than with dabigatran, as was all-cause mortality and gastrointestinal bleeding. Rivaroxaban was comparable to warfarin for major bleeding, with an increased risk in gastrointestinal bleeding and decreased risk of intracranial hemorrhage.
Casting Aspersions, Writing a Kingdom: Sexual Slander and Political Rhetoric in 2 Sam 3:6-11, 2 Sam 6:16; 20-23, and 1 Kgs 2:13-25
Authors: Fleming Erin E.
Published: February 2017

In the story of King David found in 1 Sam 16-1 Kgs 2, several episodes recount a sexual(ized) allegation made against a significant character: Ishbosheth accuses Abner of having relations with his father Saul’s consort in 2 Sam 3:6-11; Michal disparages David for flaunting himself during the cultic procession of the ark in 2 Sam 6:16; 20-23; and Solomon executes his half-brother Adonijah for requesting marriage to David’s former ‘attendant’ Abishag in 1 Kgs 2:13-25. This paper will argue that 2 Sam 3:6-11, 2 Sam 6:16; 20-23, and 1 Kgs 2:13-25 function as historiographic slander and serve the strategic literary purposes of the David narrative by providing explanations for political fallout between particular characters while simultaneously defending the moral stature of the kings David and Solomon.
The Ethics of Wicked Problems
Authors: Bauman Whitney A.
Published: February 2017

Wicked problems call for more complex thinking than many of our ethical problem-solving traditions are equipped to deal with. Multi-generational, multi-causal problems with no single solution call on us to think ethics in a new way. This article explores three such facets of what it might mean to live through and with climate change and think ethically about such changes. The reality of our planetary problems and lives might better be addressed using models based upon entanglement, multiple causality, and multiple understandings of time (“rainbow” time).