Summary Background Understanding potential patterns in future population levels is crucial for anticipating and planning for changing age structures, resource and health-care needs, and environmental and economic landscapes. Future fertility patterns are a key input to estimation of future population size, but they are surrounded by substantial uncertainty and diverging methodologies of estimation and forecasting, leading to important differences in global population projections. Changing population size and age structure might have profound economic, social, and geopolitical impacts in many countries. In this study, we developed novel methods for forecasting mortality, fertility, migration, and population. We also assessed potential economic and geopolitical effects of future demographic shifts. Methods We modelled future population in reference and alternative scenarios as a function of fertility, migration, and mortality rates. We developed statistical models for completed cohort fertility at age 50 years (CCF50). Completed cohort fertility is much more stable over time than the period measure of the total fertility rate (TFR). We modelled CCF50 as a time-series random walk function of educational attainment and contraceptive met need. Age-specific fertility rates were modelled as a function of CCF50 and covariates. We modelled age-specific mortality to 2100 using underlying mortality, a risk factor scalar, and an autoregressive integrated moving average (ARIMA) model. Net migration was modelled as a function of the Socio-demographic Index, crude population growth rate, and deaths from war and natural disasters; and use of an ARIMA model. The model framework was used to develop a reference scenario and alternative scenarios based on the pace of change in educational attainment and contraceptive met need. We estimated the size of gross domestic product for each country and territory in the reference scenario. Forecast uncertainty intervals (UIs) incorporated uncertainty propagated from past data inputs, model estimation, and forecast data distributions. Findings The global TFR in the reference scenario was forecasted to be 1·66 (95% UI 1·33–2·08) in 2100. In the reference scenario, the global population was projected to peak in 2064 at 9·73 billion (8·84–10·9) people and decline to 8·79 billion (6·83–11·8) in 2100. The reference projections for the five largest countries in 2100 were India (1·09 billion [0·72–1·71], Nigeria (791 million [594–1056]), China (732 million [456–1499]), the USA (336 million [248–456]), and Pakistan (248 million [151–427]). Findings also suggest a shifting age structure in many parts of the world, with 2·37 billion (1·91–2·87) individuals older than 65 years and 1·70 billion (1·11–2·81) individuals younger than 20 years, forecasted globally in 2100. By 2050, 151 countries were forecasted to have a TFR lower than the replacement level (TFR <2·1), and 183 were forecasted to have a TFR lower than repl...

Identification of carotid artery atherosclerosis is conventionally based on measurements of luminal stenosis and surface irregularities using in vivo imaging techniques including sonography, CT and MR angiography, and digital subtraction angiography. However, histopathologic studies demonstrate considerable differences between plaques with identical degrees of stenosis and indicate that certain plaque features are associated with increased risk for ischemic events. The ability to look beyond the lumen using highly developed vessel wall imaging methods to identify plaque vulnerable to disruption has prompted an active debate as to whether a paradigm shift is needed to move away from relying on measurements of luminal stenosis for gauging the risk of ischemic injury. Further evaluation in randomized clinical trials will help to better define the exact role of plaque imaging in clinical decision-making. However, current carotid vessel wall imaging techniques can be informative. The goal of this article is to present the perspective of the ASNR Vessel Wall Imaging Study Group as it relates to the current status of arterial wall imaging in carotid artery disease.

Key Words: Cav1.2 channels Ⅲ PKC Ⅲ calmodulin Ⅲ arrhythmias V oltage-gated L-Type (Cav1.2) Ca 2ϩ channels are expressed in the surface membrane of neurons and muscle cells, where they regulate multiple processes including excitability, contraction, gene expression, and memory storage. [1][2][3][4] Recent studies have revealed an unexpected feature of Cav1.2 channels: their activity (ie, open probability, P o ) varies within the cell membrane. [5][6][7] Low activity Cav1.2 channels open randomly and infrequently at rest, producing brief elevations in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) called "Ca 2ϩ sparklets." 8 In contrast, small clusters of Cav1.2 channels can function in a high open probability mode that generates localized zones of relatively high Ca 2ϩ influx ("persistent Ca 2ϩ sparklets"). Although targeting of protein kinase (PK)C␣ to the surface membrane by the kinase anchoring protein AKAP150 (the rodent ortholog of human AKAP79) increases the probability of persistent Cav1.2 channel activity, 9 the mechanisms by which small clusters of these channels open concertedly are unknown. Here, we used fluorescence resonance energy transfer (FRET) approaches in combination with optical and electrophysiological recordings of Ca 2ϩ influx via Cav1.2 channels to investigate this important issue. Our data indicate that activators of PKC␣, calmodulin (CaM) antagonists, or a specific Cav1.2 channel mutation that causes arrhythmias and autism in humans with the Timothy syndrome (TS) move the ubiquitous Ca 2ϩ -binding protein CaM from the IQ domain in the C-terminal tail of the channel. This induces functional interactions between nearby Cav1.2 channel via their C termini that could lead to coupled gating of these channels. MethodsAn expanded Methods section is available in the Online Data Supplement at http://circres.ahajournals.org. Isolation of Arterial and Adult and Neonatal Cardiac MyocytesMice and rats were euthanized as approved by the University of Washington Institutional Animal Care and Use Committee. Adult arterial myocytes and neonatal cardiac myocytes were prepared as described previously. 5,10 Cav1.2 and Calmodulin Constructs and Inducible PKC␣ Translocation System and Their Expression in tsA-201 CellsWe transfected tsA-201 cells using JetPEI (Polyplus Transfection) with plasmids encoding calcium channel pore-forming and accessory subunits as well as CaM. We generated the rabbit homolog of the human TS Cav1.2 (G436R, rabbit; G406R human Coupled Markov Chain ModelWe implemented a coupled Markov chain model in Matlab to determine the coupling coefficient () among Cav1.2 channels underlying membrane currents and Ca 2ϩ sparklet sites. The model was originally developed by Chung and Kennedy 14 to analyze individual records of partially coupled GABA-activated chloride channels. Electrophysiology, Confocal, and Total Internal Reflection Fluorescence MicroscopyVoltage-clamp experiments were performed using standard patchclamp techniques. Total internal reflection fluorescence (TIRF) images were...

Vasa vasorum in the adventitia of atherosclerotic arteries may play a role in plaque progression. In this investigation, a method for characterizing vasa vasorum in the carotid artery is proposed, in which the perfusion properties of the adventitia are probed via dynamic contrast-enhanced (DCE) MRI. A parametric "vasa vasorum image" is automatically generated that depicts the plasma volume (v p ) and transfer constant (K trans ). The average K trans within the adventitia is proposed as a quantitative measurement related to the extent of the vasa vasorum. In 25 subjects with lesions meeting the requirements for carotid endarterectomy (CEA) significantly higher adventitial K trans of 0.155 ؎ 0.045 min -1 was observed, compared to 0.122 ؎ 0.029 min -1 in the remaining 20 subjects with moderate disease (P < 0.01). In the 25 subjects with endarterectomy specimens, histological evaluation showed that adventitial K trans was significantly correlated with the amount of neovasculature (R ‫؍‬ 0.41; P ‫؍‬ 0.04) and macrophages (R ‫؍‬ 0.49; P ‫؍‬ 0.01) in the excised plaque. In the remaining 20 subjects without histology, elevated adventitial K trans was significantly correlated with the log of C-reactive protein (CRP) levels (R ‫؍‬ 0.57; P ‫؍‬ 0.01) and was elevated in active smokers compared to nonsmokers Recent investigations with ultrasound contrast agents have led to the concept of imaging the vasa vasorum (1,2), which are the vessels found in the adventitial layer of arteries such as the carotid artery. In ultrasound, real-time images of microbubble contrast agents passing through the vasa vasorum are converted into colorized displays of enhancement, thought to represent the local microvessel density. Characterizing the vasa vasorum is of considerable clinical interest because neovasculature arising from the vasa vasorum plays a significant role in atherosclerotic plaque progression and destabilization (3-6).Magnetic resonance imaging (MRI) with injected contrast agents offers a potential alternative to ultrasound for characterizing the adventitial vasa vasorum. Given the high accuracy of MRI for measuring plaque size (7-9) and composition (10 -12) in large arteries, an MRI technique for visualizing adventitial vasa vasorum would be beneficial for studies of factors that influence plaque progression and disruption. In this investigation, we sought to develop a visualization technique for adventitial vasa vasorum based on dynamic contrast-enhanced (DCE) MRI. Derivation of contrast agent kinetic parameters, such as the transfer constant K trans , from DCE-MRI has previously enabled investigators to probe the perfusion properties of tumors (13-15), skeletal muscle (16), and atherosclerotic plaques (17,18). We therefore propose that DCE-MRI can be used to probe the vascularity of the adventitia.One difficulty in validating this approach is the lack of a histological reference for the vasa vasorum. Use of human endarterectomy specimens for validation is indirect, as the adventitial layer is not removed with the plaque spec...