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Background Gadolinium-based contrast agents were not approved in the United States for detecting coronary artery disease (CAD) prior to the current studies. Objectives The purpose of this study was to determine the sensitivity and specificity of gadobutrol for detection of CAD by assessing myocardial perfusion and late gadolinium enhancement (LGE) imaging. Methods Two international, single-vendor, phase 3 clinical trials of near identical design, “GadaCAD1” and “GadaCAD2,” were performed. Cardiovascular magnetic resonance (CMR) included gadobutrol-enhanced first-pass vasodilator stress and rest perfusion followed by LGE imaging. CAD was defined by quantitative coronary angiography (QCA) but computed tomography coronary angiography could exclude significant CAD. Results Because the design and results for GadaCAD1 (n = 376) and GadaCAD2 (n = 388) were very similar, results were summarized as a fixed-effect meta-analysis (n = 764). The prevalence of CAD was 27.8% defined by a ≥70% QCA stenosis. For detection of a ≥70% QCA stenosis, the sensitivity of CMR was 78.9%, specificity was 86.8%, and area under the curve was 0.871. The sensitivity and specificity for multivessel CAD was 87.4% and 73.0%. For detection of a 50% QCA stenosis, sensitivity was 64.6% and specificity was 86.6%. The optimal threshold for detecting CAD was a ≥67% QCA stenosis in GadaCAD1 and ≥63% QCA stenosis in GadaCAD2. Conclusions Vasodilator stress and rest myocardial perfusion CMR and LGE imaging had high diagnostic accuracy for CAD in 2 phase 3 clinical trials. These findings supported the U .S. Food and Drug Administration approval of gadobutrol-enhanced CMR (0.1 mmol/kg) to assess myocardial perfusion and LGE in adult patients with known or suspected CAD.

We recently reported that RNAi-mediated off-target effects are important drivers of the hepatotoxicity observed for a subset of GalNAc–siRNA conjugates in rodents, and that these findings could be mitigated by seed-pairing destabilization using a single GNA nucleotide placed within the seed region of the guide strand. Here, we report further investigation of the unique and poorly understood GNA/RNA cross-pairing behavior to better inform GNA-containing siRNA design. A reexamination of published GNA homoduplex crystal structures, along with a novel structure containing a single (S)-GNA-A residue in duplex RNA, indicated that GNA nucleotides universally adopt a rotated nucleobase orientation within all duplex contexts. Such an orientation strongly affects GNA-C and GNA-G but not GNA-A or GNA-T pairing in GNA/RNA heteroduplexes. Transposition of the hydrogen-bond donor/acceptor pairs using the novel (S)-GNA-isocytidine and -isoguanosine nucleotides could rescue productive base-pairing with the complementary G or C ribonucleotides, respectively. GalNAc-siRNAs containing these GNA isonucleotides showed an improved in vitro activity, a similar improvement in off-target profile, and maintained in vivo activity and guide strand liver levels more consistent with the parent siRNAs than those modified with isomeric GNA-C or -G, thereby expanding our toolbox for the design of siRNAs with minimized off-target activity.

The purpose of this study was to assess potential gender differences in size of the lateral and medial trochlea of the male and female knee as well as the variation within gender of potential osteochondral autograft transfer (OAT) donor site area. Two hundred and twelve skeletally mature patients, 106 males and 106 females, who underwent a 3T magnetic resonance imaging of the knee for a variety of indications were utilized for analysis. Exclusion criteria included degenerative arthritis, trochlear dysplasia, and poor image quality. Medial and lateral femoral trochlear cartilage width was obtained using a linear radiologic measurement tool. Widths were measured from a reproducible anatomic location representing the maximal trochlear dimension in a region where donor plugs are commonly harvested. Trochlear width was also plotted as a function of patient height. Statistical analysis was performed using a two-sample t-test. The mean and standard deviation of the lateral trochlear cartilage width (mm) for males and females were 23.38 +/− 2.14 and 20.44 +/− 2.16, respectively (p

Multiple regions in the human brain are dedicated to accomplish the feat of object recognition; yet our brains must also compute the 2D and 3D locations of the objects we encounter in order to make sense of our visual environments. A number of studies have explored how various object category-selective regions are sensitive to and have preferences for specific 2D spatial locations in addition to processing their preferred-stimulus categories, but there is no survey of how these regions respond to depth information. In a blocked functional MRI experiment, subjects viewed a series of category-specific (i.e., faces, objects, scenes) and unspecific (e.g., random moving dots) stimuli with red/green anaglyph glasses. Critically, these stimuli were presented at different depth planes such that they appeared in front of, behind, or at the same (i.e., middle) depth plane as the fixation point (Experiment 1) or simultaneously in front of and behind fixation (i.e., mixed depth; Experiment 2). Comparisons of mean response magnitudes between back, middle, and front depth planes reveal that face and object regions OFA and LOC exhibit a preference for front depths, and motion area MT+ exhibits a strong linear preference for front, followed by middle, followed by back depth planes. In contrast, scene-selective regions PPA and OPA prefer front and/or back depth planes (relative to middle). Moreover, the occipital place area demonstrates a strong preference for “mixed” depth above and beyond back alone, raising potential implications about its particular role in scene perception. Crucially, the observed depth preferences in nearly all areas were evoked irrespective of the semantic stimulus category being viewed. These results reveal that the object category-selective regions may play a role in processing or incorporating depth information that is orthogonal to their primary processing of object category information.

Bioprosthetic aortic valve degeneration is increasingly common, often unheralded, and can have catastrophic consequences.The authors sought to assess whetherExplanted degenerate bioprosthetic valves were examined ex vivo. Patients with bioprosthetic aortic valves were recruited into 2 cohorts with and without prosthetic valve dysfunction and underwent in vivo contrast-enhanced CT angiography,All ex vivo, degenerate bioprosthetic valves displayed

Surgical repair of articular cartilage defects in the knee currently utilizes surgical algorithms based on absolute defect size. These algorithms, which have not been validated, are currently utilized not only by surgeons but also by insurance carriers for justification of reimbursement policy. However, current algorithms do not account for morphological differences between individual patients and defect size relative to condylar dimension. We hypothesized that a significant difference in relative defect size compared with condylar dimension may exist between individuals. A 3T magnetic resonance imaging from 220 skeletally mature patients, 110 males and 110 females, were analyzed. Exclusion criteria included degenerative arthritis, anatomical defects, poor image quality, and genetic abnormalities such as dwarfism. Utilizing a radiological curved measurement probe, the femoral condylar articular width was obtained for both the medial and lateral condyles. The mean condylar width from a reproducible anatomic location representing the maximal condylar dimension was measured. Statistical analysis was performed using a two-sample t-test. The lateral condyle articular cartilage width (mm) for males and females was 31.62 ± 3.54 and 26.53 ± 3.70, respectively (p

Cardiovascular imaging has largely focused on identifying structural, functional, and metabolic changes in the heart. The ability to reliably assess disease activity would have major potential clinical advantages, including the identification of early disease, differentiating active from stable conditions, and monitoring disease progression or response to therapy. Positron emission tomography (PET) imaging now allows such assessments of disease activity to be acquired in the heart, whereas magnetic resonance (MR) scanning provides detailed anatomic imaging and tissue characterization. Hybrid MR/PET scanners therefore combine the strengths of 2 already powerful imaging modalities. Simultaneous acquisition of the 2 scans also provides added benefits, including improved scanning efficiency, motion correction, and partial volume correction. Radiation exposure is lower than with hybrid PET/computed tomography scanning, which might be particularly beneficial in younger patients who may need repeated scans. The present review discusses the expanding clinical literature investigating MR/PET imaging, highlights its advantages and limitations, and explores future potential applications.

In complex real-world scenes, image content is conveyed by a large collection of intertwined visual features. The visual system disentangles these features in order to extract information about image content. Here, we investigate the role of one integral component: the content of spatial frequencies in an image. Specifically, we measure the amount of image content carried by low versus high spatial frequencies for the representation of real-world scenes in scene-selective regions of human visual cortex. To this end, we attempted to decode scene categories from the brain activity patterns of participants viewing scene images that contained the full spatial frequency spectrum, only low spatial frequencies, or only high spatial frequencies, all carefully controlled for contrast and luminance. Contrary to the findings from numerous behavioral studies and computational models that have highlighted how low spatial frequencies preferentially encode image content, decoding of scene categories from the scene-selective brain regions, including the parahippocampal place area (PPA), was significantly more accurate for high than low spatial frequency images. In fact, decoding accuracy was just as high for high spatial frequency images as for images containing the full spatial frequency spectrum in scene-selective areas PPA, RSC, OPA and object selective area LOC. We also found an interesting dissociation between the posterior and anterior subdivisions of PPA: categories were decodable from both high and low spatial frequency scenes in posterior PPA but only from high spatial frequency scenes in anterior PPA; and spatial frequency was explicitly decodable from posterior but not anterior PPA. Our results are consistent with recent findings that line drawings, which consist almost entirely of high spatial frequencies, elicit a neural representation of scene categories that is equivalent to that of full-spectrum color photographs. Collectively, these findings demonstrate the importance of high spatial frequencies for conveying the content of complex real-world scenes.

Percutaneous coronary intervention (PCI) relieves angina in patients with stable ischemic heart disease, but clinical trials have not shown that it improves survival. Between June 1999 and January 2004, we randomly assigned 2287 patients with stable ischemic heart disease to an initial management strategy of optimal medical therapy alone (medical-therapy group) or optimal medical therapy plus PCI (PCI group) and did not find a significant difference in the rate of survival during a median follow-up of 4.6 years. We now report the rate of survival among the patients who were followed for up to 15 years.We obtained permission from the patients at the Department of Veterans Affairs (VA) sites and some non-VA sites in the United States to use their Social Security numbers to track their survival after the original trial period ended. We searched the VA national Corporate Data Warehouse and the National Death Index for survival information and the dates of death from any cause. We calculated survival according to the Kaplan-Meier method and used a Cox proportional-hazards model to adjust for significant between-group differences in baseline characteristics.Extended survival information was available for 1211 patients (53% of the original population). The median duration of follow-up for all patients was 6.2 years (range, 0 to 15); the median duration of follow-up for patients at the sites that permitted survival tracking was 11.9 years (range, 0 to 15). A total of 561 deaths (180 during the follow-up period in the original trial and 381 during the extended follow-up period) occurred: 284 deaths (25%) in the PCI group and 277 (24%) in the medical-therapy group (adjusted hazard ratio, 1.03; 95% confidence interval, 0.83 to 1.21; P=0.76).During an extended-follow-up of up to 15 years, we did not find a difference in survival between an initial strategy of PCI plus medical therapy and medical therapy alone in patients with stable ischemic heart disease. (Funded by the VA Cooperative Studies Program and others; COURAGE ClinicalTrials.gov number, NCT00007657.).

This study examined the effects that the acoustic-phonetic structure of a stimulus exerts on the processes by which lexical candidates compete for activation. An auditory lexical decision paradigm was used to investigate whether shortening the VOT of an initial voiceless stop consonant in a real word results in the activation of the lexical-semantic network of its voiced competitor, i.e., does acoustically modified time prime penny via dime. Results for normal subjects showed semantic priming for related pairs and mediated priming for voiced competitors, consistent with cascade models of language processing allowing for interaction between phonological and semantic levels of processing. Although Broca's aphasics showed semantic priming (dime primed penny), they failed to show priming in the context of a lexical competitor. These results are consistent with the hypothesis that these patients have a lexical processing deficit characterized by an overall reduction in lexical activation.

The goal of this work was to determine whether rheolytic thrombectomy (RT) as an adjunct to primary percutaneous coronary intervention (PCI) reduces infarction size and improves myocardial perfusion during treatment of ST-segment elevation myocardial infarction (STEMI).Primary PCI for STEMI achieves brisk epicardial flow in most patients, but myocardial perfusion often remains suboptimal. Distal embolization of thrombus during treatment may be a contributing factor.This prospective, multicenter trial enrolled 480 patients presenting within 12 h of symptom onset and randomized to treatment with RT as an adjunct to PCI (n = 240) or to PCI alone (n = 240). Visible thrombus was not required. The primary end point was infarct size measured by sestamibi imaging at 14 to 28 days. Secondary end points included final Thrombolysis In Myocardial Infarction (TIMI) flow grade, tissue myocardial perfusion (TMP) blush, ST-segment resolution, and major adverse cardiac events (MACE), defined as the occurrence of death, new Q-wave myocardial infarction, emergent coronary artery bypass grafting, target lesion revascularization, stroke, or stent thrombosis at 30 days.Final infarct size was higher in the adjunct RT group compared with PCI alone (9.8 +/- 10.9% vs. 12.5 +/- 12.13%; p = 0.03). Final TIMI flow grade 3 was lower in the adjunct RT group (91.8% vs. 97.0% in the PCI alone group; p0.02), although fewer patients had baseline TIMI flow grade 3 in the adjunct RT group (44% vs. 63% in the PCI alone group; p0.05). There were no significant differences in TMP blush scores or ST-segment resolution. Thirty-day MACE was higher in the adjunct RT group (6.7% vs. 1.7% in the PCI alone group; p = 0.01), a difference primarily driven by very low mortality rate in patients treated with PCI alone (0.8% vs. 4.6% in patients treated with adjunct RT; p = 0.02).Despite effective thrombus removal, RT with primary PCI did not reduce infarct size or improve TIMI flow grade, TMP blush, ST-segment resolution, or 30-day MACE.