A high-density and high-confinement tokamak plasma regime for fusion energy.

The tokamak approach, utilizing a toroidal magnetic field configuration to confine a hot plasma, is one of the most promising designs for developing reactors that can exploit nuclear fusion to generate electrical energy1,2. To reach the goal of an economical reactor, most tokamak reactor designs3-10 simultaneously require reaching a plasma line-averaged density above an empirical limit-the so-called Greenwald density11-and attaining an energy confinement quality better than the standard high-confinement mode12,13. However, such an operating regime has never been verified in experiments. In addition, a long-standing challenge in the high-confinement mode has been the compatibility between a high-performance core and avoiding large, transient edge perturbations that can cause very high heat loads on the plasma-facing-components in tokamaks. Here we report the demonstration of stable tokamak plasmas with a line-averaged density approximately 20% above the Greenwald density and an energy confinement quality of approximately 50% better than the standard high-confinement mode, which was realized by taking advantage of the enhanced suppression of turbulent transport granted by high density-gradients in the high-poloidal-beta scenario14,15. Furthermore, our experimental results show an integration of very low edge transient perturbations with the high normalized density and confinement core. The operating regime we report supports some critical requirements in many fusion reactor designs all over the world and opens a potential avenue to an operating point for producing economically attractive fusion energy.

Integration of full divertor detachment with improved core confinement for tokamak fusion plasmas.

Divertor detachment offers a promising solution to the challenge of plasma-wall interactions for steady-state operation of fusion reactors. Here, we demonstrate the excellent compatibility of actively controlled full divertor detachment with a high-performance (ßN ~ 3, H98 ~ 1.5) core plasma, using high-ßp (poloidal beta, ßp > 2) scenario characterized by a sustained core internal transport barrier (ITB) and a modest edge transport barrier (ETB) in DIII-D tokamak. The high-ßp high-confinement scenario facilitates divertor detachment which, in turn, promotes the development of an even stronger ITB at large radius with a weaker ETB. This self-organized synergy between ITB and ETB, leads to a net gain in energy confinement, in contrast to the net confinement loss caused by divertor detachment in standard H-modes. These results show the potential of integrating excellent core plasma performance with an efficient divertor solution, an essential step towards steady-state operation of reactor-grade plasmas.

First Evidence of Local E×B Drift in the Divertor Influencing the Structure and Stability of Confined Plasma near the Edge of Fusion Devices.

The structure of the edge plasma in a magnetic confinement system has a strong impact on the overall plasma performance. We uncover for the first time a magnetic-field-direction dependent density shelf, i.e., local flattening of the density radial profile near the magnetic separatrix, in high confinement plasmas with low edge collisionality in the DIII-D tokamak. The density shelf is correlated with a doubly peaked density profile near the divertor target plate, which tends to occur for operation with the ion B×∇B drift direction away from the X-point, as currently employed for DIII-D advanced tokamak scenarios. This double-peaked divertor plasma profile is connected via the E×B drifts, arising from a strong radial electric field induced by the radial electron temperature gradient near the divertor target. The drifts lead to the reversal of the poloidal flow above the divertor target, resulting in the formation of the density shelf. The edge density shelf can be further enhanced at higher heating power, preventing large, periodic bursts of the plasma, i.e., edge-localized modes, in the edge region, consistent with ideal magnetohydrodynamics calculations.

Management of acute and chronic iliofemoral venous outflow obstruction: a multidisciplinary team consensus.

The aim of this manuscript was to establish a consensus for the management of acute and chronic venous obstruction among specialists in the UK. Specialist physicians representing vascular surgery, interventional radiology and hematology were invited to 3 meetings to discuss management of acute and chronic iliofemoral obstruction. The meetings outlined controversial areas, included a topic-by-topic review; and on completion reached a consensus when greater than 80% agreement was reached on each topic. Physicians from 19 UK hospitals agreed on treatment protocols and highlighted areas that need development. Potential standard treatment algorithms were created. It was decided to establish a national registry of venous patients led by representatives from the treating multidisciplinary teams. Technical improvements have facilitated invasive treatment of patients with acute and chronic venous obstruction; however, the evidence guiding treatment is weak. Treatment should be conducted in centers with multi-disciplinary input; robust, coordinated data collection; and regular outcome analysis to ensure safe and effective treatment and a basis for future evolvement.

Formation of a High Pressure Staircase Pedestal with Suppressed Edge Localized Modes in the DIII-D Tokamak.

We observe the formation of a high-pressure staircase pedestal (≈16-20 kPa) in the DIII-D tokamak when large amplitude edge localized modes are suppressed using resonant magnetic perturbations. The staircase pedestal is characterized by a flattening of the density and temperature profiles in midpedestal creating a two-step staircase pedestal structure correlated with the appearance of midpedestal broadband fluctuations. The pedestal oscillates between the staircase and single-step structure every 40-60 ms, correlated with oscillations in the heat and particle flux to the divertor. Gyrokinetic analysis using the cgyro code shows that when the heat and particle flux to the divertor decreases, the pedestal broadens and the E×B shear at the midpedestal decreases, triggering a transport bifurcation from the kinetic ballooning mode (KBM) to trapped electron mode (TEM) limited transport that flattens the density and temperature profiles at midpedestal and results in the formation of the staircase pedestal. As the heat flux to the divertor increases, the pedestal narrows and the E×B shear at the midpedestal increases, triggering a back transition from TEM to KBM limited transport. The pedestal pressure increases during the staircase phase, indicating that enhanced midpedestal turbulence can be beneficial for confinement.

E×B Flux Driven Detachment Bifurcation in the DIII-D Tokamak.

A bifurcative step transition from low-density, high-temperature, attached divertor conditions to high-density, low-temperature, detached divertor conditions is experimentally observed in DIII-D tokamak plasmas as density is increased. The step transition is only observed in the high confinement mode and only when the B×∇B drift is directed towards the divertor. This work reports for the first time a theoretical explanation and numerical simulations that qualitatively reproduce this bifurcation and its dependence on the toroidal field direction. According to the model, the bifurcation is primarily driven by the interdependence of the E×B-drift fluxes, divertor electric potential structure, and divertor conditions. In the attached conditions, strong potential gradients in the low field side (LFS) divertor drive E×B-drift flux towards the high field side divertor, reinforcing low density, high temperature conditions in the LFS divertor leg. At the onset of detachment, reduction in the potential gradients in the LFS divertor leg reduce the E×B-drift flux as well, such that the divertor plasma evolves nonlinearly to high density, strongly detached conditions. Experimental estimates of the E×B-drift fluxes, based on divertor Thomson scattering measurements, and their dependence on the divertor conditions are qualitatively consistent with the numerical predictions. The implications for divertor power exhaust and detachment control in the next step fusion devices are discussed.

Pedestal bifurcation and resonant field penetration at the threshold of edge-localized mode suppression in the DIII-D Tokamak.

Rapid bifurcations in the plasma response to slowly varying n=2 magnetic fields are observed as the plasma transitions into and out of edge-localized mode (ELM) suppression. The rapid transition to ELM suppression is characterized by an increase in the toroidal rotation and a reduction in the electron pressure gradient at the top of the pedestal that reduces the perpendicular electron flow there to near zero. These events occur simultaneously with an increase in the inner-wall magnetic response. These observations are consistent with strong resonant field penetration of n=2 fields at the onset of ELM suppression, based on extended MHD simulations using measured plasma profiles. Spontaneous transitions into (and out of) ELM suppression with a static applied n=2 field indicate competing mechanisms of screening and penetration of resonant fields near threshold conditions. Magnetic measurements reveal evidence for the unlocking and rotation of tearinglike structures as the plasma transitions out of ELM suppression.

Surface microcracks signal osteoblasts to regulate alignment and bone formation.

Microcracks are present in bone and can result from fatigue damage due to repeated, cyclically applied stresses. From a mechanical point, microcracks can dissipate strain energy at the advancing tip of a crack to improve overall bone toughness. Physiologically, microcracks are thought to trigger bone remodeling. Here, we examine the effect of microcracks specifically on osteoblasts, which are bone-forming cells, by comparing cell responses on microcracked versus non-microcracked hydroxyapatite (HA) specimens. Osteoblast attachment was found to be greater on microcracked HA specimens (p<0.05). More importantly, we identified the preferential alignment of osteoblasts in the direction of the microcracks on HA. Cells also displayed a preferential attachment that was 75 to 90 µm away from the microcrack indent. After 21 days of culture, osteoblast maturation was notably enhanced on the HA with microcracks, as indicated by increased alkaline phosphatase activity and gene expression. Furthermore, examination of bone deposition by confocal laser scanning microscopy indicated preferential mineralization at microcrack indentation sites. Dissolution studies indicate that the microcracks increase calcium release, which could contribute to osteoblast responses. Our findings suggest that microcracks signal osteoblast attachment and bone formation/healing.

Dynamic Interactive Educational Diabetes Simulations Using the World Wide Web: An Experience of More Than 15 Years with AIDA Online.

Background. AIDA is a widely available downloadable educational simulator of glucose-insulin interaction in diabetes. Methods. A web-based version of AIDA was developed that utilises a server-based architecture with HTML FORM commands to submit numerical data from a web-browser client to a remote web server. AIDA online, located on a remote server, passes the received data through Perl scripts which interactively produce 24 hr insulin and glucose simulations. Results. AIDA online allows users to modify the insulin regimen and diet of 40 different prestored "virtual diabetic patients" on the internet or create new "patients" with user-generated regimens. Multiple simulations can be run, with graphical results viewed via a standard web-browser window. To date, over 637,500 diabetes simulations have been run at AIDA online, from all over the world. Conclusions. AIDA online's functionality is similar to the downloadable AIDA program, but the mode of implementation and usage is different. An advantage to utilising a server-based application is the flexibility that can be offered. New modules can be added quickly to the online simulator. This has facilitated the development of refinements to AIDA online, which have instantaneously become available around the world, with no further local downloads or installations being required.

Initial results of the high resolution edge Thomson scattering upgrade at DIII-D.

Validation of models of pedestal structure is an important part of predicting pedestal height and performance in future tokamaks. The Thomson scattering diagnostic at DIII-D has been upgraded in support of validating these models. Spatial and temporal resolution, as well as signal to noise ratio, have all been specifically enhanced in the pedestal region. This region is now diagnosed by 20 view-chords with a spacing of 6 mm and a scattering length of just under 5 mm sampled at a nominal rate of 250 Hz. When mapped to the outboard midplane, this corresponds to ~3 mm spacing. These measurements are being used to test critical gradient models, in which pedestal gradients increase in time until a threshold is reached. This paper will describe the specifications of the upgrade and present initial results of the system.

Thomson scattering diagnostic upgrade on DIII-D.

The DIII-D Thomson scattering system has been upgraded. A new data acquisition hardware was installed, adding the capacity for additional spatial channels and longer acquisition times for temperature and density measurements. Detector modules were replaced with faster transimpedance circuitry, increasing the signal-to-noise ratio by a factor of 2. This allows for future expansion to the edge system. A second phase upgrade scheduled for 2010-2011 includes the installation of four 1 J/pulse Nd:YAG lasers at 50 Hz repetition rate. This paper presents the first completed phase of the upgrade and performance comparison between the original system and the upgraded system. The plan for the second phase is also presented.

Outcomes of natural cycles versus programmed cycles for 1677 frozen-thawed embryo transfers.

The study compares outcomes for patients with frozen embryos who had frozen-thawed embryo transfer (FET) timed to their natural ovulation cycle versus cycles in which endometrial timing was programmed with oestrogen and progesterone. A total of 1205 patients undergoing 1677 FET cycles between 1 January 2000 and 31 December 2006 were analysed. Comparisons were made for patients undergoing modified natural versus programmed FET cycles, as well as between patients using their own eggs for frozen embryos versus those using donor-egg-derived embryos. Clinical pregnancy (gestational sac on 7 week ultrasound) rates (CPR), as well as miscarriage rates, were significantly higher in programmed FET cycles in patients using their own eggs (106/262, 40.5% per embryo transfer, P = 0.015) However, there was not a difference in delivered pregnancies between cycle types in own egg patients (natural cycle delivery rate 245/862, 28.4%; programmed cycle delivery rate 77/262, 29.4%). Furthermore, CPR were not different in natural (38/129, 29.5%) versus programmed cycles (144/424, 34.0%) for ovum donor recipients, nor were delivered pregnancy rates different in natural (33/129, 25.6%) versus programmed cycles (114/424, 26.9%) for ovum donor recipients. In conclusion, there is no significant difference in delivery rates for FET in natural (278/991, 28.1%) versus programmed (191/686, 27.8%) cycles using both own embryos and donor-egg-derived embryos.

Incorporating a generic model of subcutaneous insulin absorption into the AIDA v4 diabetes simulator. 3. Early plasma insulin determinations.

INTRODUCTION: AIDA is an interactive educational diabetes simulator that has been available without charge via the Internet for over 12 years. Recent articles have described the incorporation of a novel generic model of insulin absorption into AIDA as a way of enhancing its capabilities. The basic model components to be integrated have been overviewed, with the aim being to provide simulations of regimens utilizing insulin analogues, as well as insulin doses greater than 40 IU (the current upper limit within the latest release of AIDA [v4.3a]). Some preliminary calculated insulin absorption results have also recently been described. METHODS: This article presents the first simulated plasma insulin profiles from the integration of the generic subcutaneous insulin absorption model, and the currently implemented model in AIDA for insulin disposition. Insulin absorption has been described by the physiologically based model of Tarín and colleagues. A single compartment modeling approach has been used to specify how absorbed insulin is distributed in, and eliminated from, the human body. To enable a numerical solution of the absorption model, a spherical subcutaneous depot for the injected insulin dose has been assumed and spatially discretized into shell compartments with homogeneous concentrations, having as its center the injection site. The number of these compartments will depend on the dose and type of insulin. Insulin inflow arises as the sum of contributions to the different shells. For this report the first bench testing of plasma insulin determinations has been done. RESULTS: Simulated plasma insulin profiles are provided for currently available insulin preparations, including a rapidly acting insulin analogue (e.g., lispro/Humalog or aspart/Novolog), a short-acting (regular) insulin preparation (e.g., Actrapid), intermediate-acting insulins (both Semilente and neutral protamine Hagedorn types), and a very long-acting insulin analogue (e.g., glargine/Lantus), as well as for insulin doses up to 50 IU. DISCUSSION: The methodology to be adopted for implementing the generic absorption model within AIDA has been overviewed, and the first plasma insulin profiles based on this approach have been demonstrated. Ideas for future work and development are discussed. It is expected that an updated release of AIDA (v4.5), based on this collaborative approach, will become available for free--in due course--via the www.2aida.org Web site. Readers who wish to be informed when the new software is launched can join the very low volume AIDA announcement list by sending a blank email note to subscribe@2aida.org.

Incorporating a generic model of subcutaneous insulin absorption into the AIDA v4 diabetes simulator: 1. a prospective collaborative development plan.

INTRODUCTION: AIDA v4 is an interactive educational diabetes simulator that has been made available, for over a decade, without charge via the Internet. The software is currently freely accessible at http://www.2aida.org. This report sets out a collaborative development plan to enhance the program with a new model of subcutaneous insulin absorption, which permits the simulation of rapidly acting and very long-acting insulin analogues, as well as insulin injection doses larger than 40 units. METHODS: A novel, generic, physiological subcutaneous insulin absorption model is overviewed and a methodology is proposed by which this can be substituted in place of the previously adopted insulin absorption model utilized within AIDA v4.3a. Apart from this substitution it is proposed to retain the existing model of the glucoregulatory system currently used in AIDA v4.3a. RESULTS: Initial simulation results based on bench testing of this approach using MATLAB are presented for the exogenous insulin flow profile (I(ex)) following subcutaneous injections of a rapidly acting insulin analogue, a short-acting (regular) insulin preparation, intermediate-acting insulins (both Semilente and neutral protamine Hagedorn types), and a very long-acting insulin analogue. DISCUSSION: It is proposed to implement this collaborative development plan-first by bench testing the approach in MATLAB and then by integrating the generic subcutaneous insulin absorption I(ex) model into the AIDA simulator in Pascal. The aim is to provide enhanced functionality and educational simulations of regimens utilizing novel insulin analogues, as well as injections larger than 40 units of insulin.

Incorporating a generic model of subcutaneous insulin absorption into the AIDA v4 diabetes simulator: 2. preliminary bench testing.

BACKGROUND: The AIDA interactive educational diabetes simulator has been available without charge for over a decade via the Internet (see www.2aida.org). Part 1 of this report [J Diabetes Sci Technol. 2007;1(3):423-35] described the model components to be integrated to enhance the utility of the software, with the aim being to provide enhanced functionality and educational simulations of regimens utilizing insulin analogues, as well as insulin doses greater than 40 units. This report provides some preliminary subcutaneous insulin absorption bench testing results for the updated modeling prototype. METHODS: An analysis has been done of the spatial distribution of insulin in the region of the injection site for different classes of insulin preparations and times after the administration of a set insulin injection. Demonstrations of the proportion of residual insulin in depot versus time after a subcutaneous bolus have also been simulated for different insulin injection volumes and concentrations, as well as to show the proportions of hexameric, dimeric, and bound insulin over time after an injection. RESULTS: Some early bench testing results are highlighted following subcutaneous injections of a rapidly acting insulin analogue (such as lispro/Humalog or aspart/NovoLog), a short-acting (regular) insulin preparation (e.g., Actrapid), intermediate-acting insulins (both Semilente and neutral protamine Hagedorn types), and a very long-acting insulin analogue (such as glargine/Lantus). The transformation, dissociation/association, and absorption processes by which insulin moves from the subcutaneous injection site to the plasma are also illustrated. DISCUSSION: This report demonstrates how enhanced capabilities may be added to AIDA once a new model of subcutaneous insulin absorption is incorporated. The revised approach, once fully implemented, should permit the simulation of plasma insulin profiles for rapidly acting and very long-acting insulin analogues, as well as insulin injections greater than 40 units.

Teaching diabetes to Middle-School students with the www.2aida.net AIDA online diabetes software simulator.

INTRODUCTION: The lifetime risk of developing diabetes for students born in the new millennium in the United States is estimated to be 27% to 52%. Many students need to learn about diabetes for their personal care, or desire to learn about diabetes to develop a career in healthcare. Most teenagers are adept at learning through Web-based computer tools. METHODS: Twenty-one students entering 8(th) and 9(th) grades (aged 12 to 14 years old) enrolled in a Biotechnology Summer Camp focused on diabetes. Lectures on pathophysiology and clinical aspects of diabetes were followed by simulated cases using the AIDA online diabetes software simulator accessed via the internet at www.2aida.net. Two cases demonstrated glycemic effects and pharmacokinetics of insulin administration, diet, and exercise in insulin-dependent (Type 1) diabetes and non-insulin-dependent (Type 2) diabetes. Students filled out standardized evaluations at the end of the session to assess receptiveness to this type of learning; opinions on the utility, information, and ease of use; and perceived risks of using the online simulator to understand diabetes. RESULTS: All students were receptive to this educational tool. The majority found AIDA online useful (17/21 [81%]), educational (21/21 [100%]), worthy of wider distribution (20/21 [95%]), and would recommend the program to others with diabetes or wanting to learn about diabetes (18/21 [86%]). A minority (2/21 [9.5%]) found the program risky regarding the information given to the students. Positive comments included the ability to visualize concepts being taught in earlier lectures, and recognized the rigors required to manage diabetes. Fewer negative comments reflected frustration with the web-based user interface, the course materials, or difficulty in achieving good simulated glycemic control. DISCUSSION: Teaching pathophysiology of diabetes and pharmacology of insulin to middle school students is enhanced with the AIDA online diabetes simulator. Future versions of this program, and development of similar programs, could be useful in teaching adolescents who have diabetes, and might help stimulate interested students to learn more about the care of people with diabetes.

Retrospective pilot feedback survey of 200 users of the AIDA Version 4 Educational Diabetes Program. 1--Quantitative Survey Data.

This column reports a detailed, questionnaire-based, post-release feedback survey of 200 users of the AIDA version 4 educational diabetes simulator. AIDA is a freeware computer program that permits the interactive simulation of plasma insulin and blood glucose profiles for educational, demonstration, self-learning, and research purposes. Since its Internet launch in 1996 over 700,000 visits have been logged to the AIDA Websites-including www.2aida.org-and over 200,000 program copies have been downloaded free-of-charge. The main goals of the current study were: (1) to establish what people have thought about the AIDA program, (2) to assess the utility of the software, and (3) to ascertain how much people have actually used it. An analysis was therefore undertaken of the first 200 feedback forms that were returned by AIDA users. The questionnaire-based survey methodology was found to be robust and reliable. Feedback forms were received from participants in 21 countries. One hundred six of 209 responses (50.7%) were received from people with diabetes, and 36 of 209 (17.2%) from relatives of patients, with lesser numbers from doctors, students, diabetes educators, nurses, pharmacists, and other end users. Please note some respondents fulfilled more than one end-user category, hence the denominator <200; for example, someone with diabetes who was also a doctor. This study has established the feasibility of using a simple feedback form to survey a substantial number of diabetes software users. In addition, it has yielded interesting data in terms of who are the main users of the AIDA program, and has also provided technical (computer) information that has aided the release of a freeware upgrade to the software. In general, users reported finding the program to be of educational value. The majority also felt it would be of interest to diabetes educators and people with diabetes. Most were clear about its limitations as a simulator-based learning tool. The implications of these findings will be discussed.

Interactive educational diabetes/insulin tutorial at www.2aida.info.

The World Wide Web now hosts a multitude of diabetes educational materials in various formats. Of particular interest is the diabetes/insulin tutorial available at the AIDA Website (accessible directly at: www.2aida.info). The tutorial combines textual or "static" information with an interactive diabetes simulator-AIDA online-to provide an engaging and effective educational tool. AIDA online (accessible directly at: www.2aida.net) enables the simulation of plasma insulin and blood glucose levels from user-defined insulin injection and carbohydrate intake data. A haemoglobin A1c value is also computed, giving an indication of overall blood glucose control in the virtual patient with diabetes. The diabetes/insulin tutorial is currently composed of four sections: the first two cover in considerable depth insulin injection regimens and insulin dosage adjustment; the third section introduces the principles of carbohydrate counting and, specifically, matching insulin doses to carbohydrate intake; and the fourth section illustrates the relationship between blood glucose levels and renal excretion of glucose. The simulator runs alongside the tutorial, and allows various concepts described in the text to be explored freely by the user and simulated interactively. This introduces a novel way of learning how injected insulin and dietary carbohydrate interact in various insulin injection regimens. A fifth section- for which any offers of assistance would be gratefully received-is planned. This will consider the use of insulin pumps and rapidly acting and very long-acting insulin analogues. Further improvements that may strengthen the existing tutorial and/or use of the online simulator are discussed in this column.

Diabetes website review: www.2aida.org.

Previous Diabetes Information Technology & WebWatch columns have addressed the use of diabetes simulators, and, in particular, aspects of the AIDA software. AIDA is a freeware computer program, which simulates the interaction of carbohydrates and insulin administered in people with insulin-dependent (type 1) diabetes mellitus. The program is intended to be used as an educational support tool, and is available via the Internet without charge from www.2aida.org. In this article, the AIDA Website is described and reviewed in terms of both content and functionality. This popular non-commercial Internet site provides free access to a downloadable PC version of AIDA, as well as access to a Web-based version of the simulator that can be run online (accessible directly at: www.2aida.net). User feedback suggests that the Website and the AIDA software have been of significant interest and value to many patients, their relatives and carers, students, and a variety of health-care professionals and researchers. The interactive and dynamic nature of the simulations adds a real-life dimension to the Web-based educational material, and the software is complemented by a substantial amount of supporting information at the Website. The on-going collection of subjective feedback continues to provide anecdotal evidence of the utility of the software, and this will hopefully be corroborated by results from more formal and objective evaluations. The future potential of diabetes simulators, in both education and research, is becoming increasingly apparent, and the AIDA Website is evolving accordingly.