Rationale and design of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary heart disease 2 trial (CE-MARC 2): a prospective, multicenter, randomized trial of diagnostic strategies in suspected coronary heart disease

Background: A number of investigative strategies exist for the diagnosis of coronary heart disease (CHD). Despite the widespread availability of noninvasive imaging, invasive angiography is commonly used early in the diagnostic pathway. Consequently, approximately 60% of angiograms reveal no evidence of obstructive coronary disease. Reducing unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. There are no large-scale comparative effectiveness trials of the different diagnostic strategies recommended in international guidelines and none that have evaluated the safety and efficacy of cardiovascular magnetic resonance.<p></p> Trial Design: CE-MARC 2 is a prospective, multicenter, 3-arm parallel group, randomized controlled trial of patients with suspected CHD (pretest likelihood 10%-90%) requiring further investigation. A total of 1,200 patients will be randomized on a 2:2:1 basis to receive 3.0-T cardiovascular magnetic resonance–guided care, single-photon emission computed tomography–guided care (according to American College of Cardiology/American Heart Association appropriate-use criteria), or National Institute for Health and Care Excellence guidelines–based management. The primary (efficacy) end point is the occurrence of unnecessary angiography as defined by a normal (>0.8) invasive fractional flow reserve. Safety of each strategy will be assessed by 3-year major adverse cardiovascular event rates. Cost-effectiveness and health-related quality-of-life measures will be performed.<p></p> Conclusions: The CE-MARC 2 trial will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intension of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, health-related quality of life, and the cost-effectiveness of CHD investigation

Heritability of risk-taking in adolescence: A longitudinal twin study

Adolescents are prone to risk-taking behaviors leading to adverse consequences such as substance abuse, accidents, violence, and victimization. However, little is known about the contribution of genetic and environmental factors to individual differences in the propensity for risk-taking. This study investigated developmental changes, longitudinal stability, and heritability of risk-taking using data from 752 adolescent twins including 169 MZ and 203 DZ pairs. The Balloon Analogue Risk Task (BART), an experimental behavioral measure of risk taking, was administered to the twins at age 12 and then re-administered to a part of this sample at age 14. Risk-taking increased with age, but individual differences showed a significant longitudinal stability. Genetic model fitting showed that at age 12, heritability of risk-taking was modest but significant in both sexes, whereas at age 14, heritability increased to 55% in males and became non-significant in females. The findings suggest that propensity for risk-taking as measured by BART can be a useful endophenotype for genetic studies of adolescent externalizing psychopathology, however, the utility of this measure may be limited by sex differences in heritability

Anti-self-dual conformal structures with null Killing vectors from projective structures

Using twistor methods, we explicitly construct all local forms of four--dimensional real analytic neutral signature anti--self--dual conformal structures $(M,[g])$ with a null conformal Killing vector. We show that $M$ is foliated by anti-self-dual null surfaces, and the two-dimensional leaf space inherits a natural projective structure. The twistor space of this projective structure is the quotient of the twistor space of $(M,[g])$ by the group action induced by the conformal Killing vector. We obtain a local classification which branches according to whether or not the conformal Killing vector is hyper-surface orthogonal in $(M, [g])$. We give examples of conformal classes which contain Ricci--flat metrics on compact complex surfaces and discuss other conformal classes with no Ricci--flat metrics.Comment: 43 pages, 4 figures. Theorem 2 has been improved: ASD metrics are given in terms of general projective structures without needing to choose special representatives of the projective connection. More examples (primary Kodaira surface, neutral Fefferman structure) have been included. Algebraic type of the Weyl tensor has been clarified. Final version, to appear in Commun Math Phy

Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+Ca^{\text{2+}} cycling

Aims Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure. Methods and results RT–qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5−/−). Before manifesting cardiac dysfunction, Atg5−/− mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high-frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load, and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5−/− cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5−/− cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload. Conclusion Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve

Thermal Infrared Radiometric Calibration of the Entire Landsat 4, 5, and 7 Archive (1982-2010)

Landsat's continuing record of the thermal state of the earth's surface represents the only long term (1982 to the present) global record with spatial scales appropriate for human scale studies (i.e., tens of meters). Temperature drives many of the physical and biological processes that impact the global and local environment. As our knowledge of, and interest in, the role of temperature on these processes have grown, the value of Landsat data to monitor trends and process has also grown. The value of the Landsat thermal data archive will continue to grow as we develop more effective ways to study the long term processes and trends affecting the planet. However, in order to take proper advantage of the thermal data, we need to be able to convert the data to surface temperatures. A critical step in this process is to have the entire archive completely and consistently calibrated into absolute radiance so that it can be atmospherically compensated to surface leaving radiance and then to surface radiometric temperature. This paper addresses the methods and procedures that have been used to perform the radiometric calibration of the earliest sizable thermal data set in the archive (Landsat 4 data). The completion of this effort along with the updated calibration of the earlier (1985 1999) Landsat 5 data, also reported here, concludes a comprehensive calibration of the Landsat thermal archive of data from 1982 to the presen