Developing an Experimental Basis for Understanding Transport in NIF Hohlraum Plasmas.

We report on the first multilocation electron temperature (T_{e}) and flow measurements in an ignition hohlraum at the National Ignition Facility using the novel technique of mid-Z spectroscopic tracer "dots." The measurements define a low resolution "map" of hohlraum plasma conditions and provide a basis for the first multilocation tests of particle and energy transport physics in a laser-driven x-ray cavity. The data set is consistent with classical heat flow near the capsule but reduced heat flow near the laser entrance hole. We evaluate the role of kinetic effects, self-generated magnetic fields, and instabilities in causing spatially dependent heat transport in the hohlraum.

Progress towards a more predictive model for hohlraum radiation drive and symmetry.

For several years, we have been calculating the radiation drive in laser-heated gold hohlraums using flux-limited heat transport with a limiter of 0.15, tabulated values of local thermodynamic equilibrium gold opacity, and an approximate model for not in a local thermodynamic equilibrium (NLTE) gold emissivity (DCA_2010). This model has been successful in predicting the radiation drive in vacuum hohlraums, but for gas-filled hohlraums used to drive capsule implosions, the model consistently predicts too much drive and capsule bang times earlier than measured. In this work, we introduce a new model that brings the calculated bang time into better agreement with the measured bang time. The new model employs (1) a numerical grid that is fully converged in space, energy, and time, (2) a modified approximate NLTE model that includes more physics and is in better agreement with more detailed offline emissivity models, and (3) a reduced flux limiter value of 0.03. We applied this model to gas-filled hohlraum experiments using high density carbon and plastic ablator capsules that had hohlraum He fill gas densities ranging from 0.06 to 1.6 mg/cc and hohlraum diameters of 5.75 or 6.72 mm. The new model predicts bang times to within ±100 ps for most experiments with low to intermediate fill densities (up to 0.85 mg/cc). This model predicts higher temperatures in the plasma than the old model and also predicts that at higher gas fill densities, a significant amount of inner beam laser energy escapes the hohlraum through the opposite laser entrance hole.

Cost-effectiveness of nonsteroidal anti-inflammatory drugs and opioids in the treatment of knee osteoarthritis in older patients with multiple comorbidities.

OBJECTIVE: To evaluate long-term clinical and economic outcomes of naproxen, ibuprofen, celecoxib or tramadol for OA patients with cardiovascular disease (CVD) and diabetes. DESIGN: We used the Osteoarthritis Policy Model to examine treatment with these analgesics after standard of care (SOC) - acetaminophen and corticosteroid injections - failed to control pain. NSAID regimens were evaluated with and without proton pump inhibitors (PPIs). We evaluated over-the-counter (OTC) regimens where available. Estimates of treatment efficacy (pain reduction, occurring in ∼57% of patients on all regimens) and toxicity (major cardiac or gastrointestinal toxicity or fractures, risk ranging from 1.09% with celecoxib to 5.62% with tramadol) were derived from published literature. Annual costs came from Red Book Online(®). Outcomes were discounted at 3%/year and included costs, quality-adjusted life expectancy, and incremental cost-effectiveness ratios (ICERs). Key input parameters were varied in sensitivity analyses. RESULTS: Adding ibuprofen to SOC was cost saving, increasing QALYs by 0.07 while decreasing cost by $800. Incorporating OTC naproxen rather than ibuprofen added 0.01 QALYs and increased costs by $300, resulting in an ICER of $54,800/QALY. Using prescription naproxen with OTC PPIs led to an ICER of $76,700/QALY, while use of prescription naproxen with prescription PPIs resulted in an ICER of $252,300/QALY. Regimens including tramadol or celecoxib cost more but added fewer QALYs and thus were dominated by several of the naproxen-containing regimens. CONCLUSIONS: In patients with multiple comorbidities, naproxen- and ibuprofen-containing regimens are more effective and cost-effective in managing OA pain than opioids, celecoxib or SOC.

Beyond the gain exponent: Effect of damping, scale length, and speckle length on stimulated scatter.

Three-dimensional wave propagation simulations and experiments show that the gain exponent, an often used metric to assess the likelihood of stimulated Brillouin scatter, is insufficient and must be augmented with another parameter, Nr, the ratio of the resonance length, Lres, to the laser speckle length. The damping rate of ion acoustic waves, ν, and thus Lres, which is proportional to ν, are easily varied with plasma species composition, e.g., by varying the ratio of hydrogen and carbon ions. As Nr decreases, stimulated Brillouin scattering increases despite the same gain exponent.

Pharmacologic regimens for knee osteoarthritis prevention: can they be cost-effective?

OBJECTIVE: We sought to determine the target populations and drug efficacy, toxicity, cost, and initiation age thresholds under which a pharmacologic regimen for knee osteoarthritis (OA) prevention could be cost-effective. DESIGN: We used the Osteoarthritis Policy (OAPol) Model, a validated state-transition simulation model of knee OA, to evaluate the cost-effectiveness of using disease-modifying OA drugs (DMOADs) as prophylaxis for the disease. We assessed four cohorts at varying risk for developing OA: (1) no risk factors, (2) obese, (3) history of knee injury, and (4) high-risk (obese with history of knee injury). The base case DMOAD was initiated at age 50 with 40% efficacy in the first year, 5% failure per subsequent year, 0.22% major toxicity, and annual cost of $1,000. Outcomes included costs, quality-adjusted life expectancy (QALE), and incremental cost-effectiveness ratios (ICERs). Key parameters were varied in sensitivity analyses. RESULTS: For the high-risk cohort, base case prophylaxis increased quality-adjusted life-years (QALYs) by 0.04 and lifetime costs by $4,600, and produced an ICER of $118,000 per QALY gained. ICERs >$150,000/QALY were observed when comparing the base case DMOAD to the standard of care in the knee injury only cohort; for the obese only and no risk factors cohorts, the base case DMOAD was less cost-effective than the standard of care. Regimens priced at $3,000 per year and higher demonstrated ICERs above cost-effectiveness thresholds consistent with current US standards. CONCLUSIONS: The cost-effectiveness of DMOADs for OA prevention for persons at high risk for incident OA may be comparable to other accepted preventive therapies.

Simple solution to the Fresnel-Kirchoff diffraction integral for application to refraction-enhanced radiography.

We present a simple solution to the Fresnel-Kirchoff diffraction integral that is appropriate for x-ray radiography of strongly absorbing and phase-shifting objects in the geometrical optics regime, where phase contrast enhancements can be considered to be caused by refraction by a semi-opaque object. We demonstrate its accuracy by comparison to brute-force numerical ray trace and diffraction calculations of a representative simulated object, and show excellent agreement for spatial scales corresponding to Fresnel numbers greater than unity. The result represents a significant improvement over approximate formulas typically used in analysis of refraction-enhanced radiographs, particularly for radiography of transient phenomena in objects that strongly refract and show significant absorption.

Onset of hydrodynamic mix in high-velocity, highly compressed inertial confinement fusion implosions.

Deuterium-tritium inertial confinement fusion implosion experiments on the National Ignition Facility have demonstrated yields ranging from 0.8 to 7×10(14), and record fuel areal densities of 0.7 to 1.3 g/cm2. These implosions use hohlraums irradiated with shaped laser pulses of 1.5-1.9 MJ energy. The laser peak power and duration at peak power were varied, as were the capsule ablator dopant concentrations and shell thicknesses. We quantify the level of hydrodynamic instability mix of the ablator into the hot spot from the measured elevated absolute x-ray emission of the hot spot. We observe that DT neutron yield and ion temperature decrease abruptly as the hot spot mix mass increases above several hundred ng. The comparison with radiation-hydrodynamic modeling indicates that low mode asymmetries and increased ablator surface perturbations may be responsible for the current performance.

Hot-spot mix in ignition-scale inertial confinement fusion targets.

Mixing of plastic ablator material, doped with Cu and Ge dopants, deep into the hot spot of ignition-scale inertial confinement fusion implosions by hydrodynamic instabilities is diagnosed with x-ray spectroscopy on the National Ignition Facility. The amount of hot-spot mix mass is determined from the absolute brightness of the emergent Cu and Ge K-shell emission. The Cu and Ge dopants placed at different radial locations in the plastic ablator show the ablation-front hydrodynamic instability is primarily responsible for hot-spot mix. Low neutron yields and hot-spot mix mass between 34(-13,+50) ng and 4000(-2970,+17 160) ng are observed.

Disease-modifying drugs for knee osteoarthritis: can they be cost-effective?

OBJECTIVE: Disease-modifying osteoarthritis drugs (DMOADs) are under development. Our goal was to determine efficacy, toxicity, and cost thresholds under which DMOADs would be a cost-effective knee OA treatment. DESIGN: We used the Osteoarthritis Policy Model, a validated computer simulation of knee OA, to compare guideline-concordant care to strategies that insert DMOADs into the care sequence. The guideline-concordant care sequence included conservative pain management, corticosteroid injections, total knee replacement (TKR), and revision TKR. Base case DMOAD characteristics included: 50% chance of suspending progression in the first year (resumption rate of 10% thereafter) and 30% pain relief among those with suspended progression; 0.5%/year risk of major toxicity; and costs of $1,000/year. In sensitivity analyses, we varied suspended progression (20-100%), pain relief (10-100%), major toxicity (0.1-2%), and cost ($1,000-$7,000). Outcomes included costs, quality-adjusted life expectancy, incremental cost-effectiveness ratios (ICERs), and TKR utilization. RESULTS: Base case DMOADs added 4.00 quality-adjusted life years (QALYs) and $230,000 per 100 persons, with an ICER of $57,500/QALY. DMOADs reduced need for TKR by 15%. Cost-effectiveness was most sensitive to likelihoods of suspended progression and pain relief. DMOADs costing $3,000/year achieved ICERs below $100,000/QALY if the likelihoods of suspended progression and pain relief were 20% and 70%. At a cost of $5,000, these ICERs were attained if the likelihoods of suspended progression and pain relief were both 60%. CONCLUSIONS: Cost, suspended progression, and pain relief are key drivers of value for DMOADs. Plausible combinations of these factors could reduce need for TKR and satisfy commonly cited cost-effectiveness criteria.

A label-free, impedance-based real time assay to identify drug-induced toxicities and differentiate cytostatic from cytotoxic effects.

Cell-based assays are key tools in drug safety assessment. However, they usually provide only limited information about time-kinetics of a toxic effect and implementing multiple measurements is often complex. To overcome these issues we established an impedance-based approach which is able to differentiate cytostatic from cytotoxic drugs by recording time-kinetics of compound-effects on cells. NIH 3T3 fibroblasts were seeded on xCELLigence® E-plates and impedance was continuously measured over 5 days. The obtained results reflected cytotoxicity and cell proliferation, as confirmed by neutral red uptake in vitro. Based on known toxicants, we established an algorithm able to discriminate cytostatic, cytotoxic and non-toxic compounds based on the shape of the impedance curves. Analyzing impedance curve patterns of additional 37 compounds allowed the identification and differentiation of these distinct effects as results correlated well with previous in vivo findings. We show that impedance-based real-time cell analysis is a convenient tool to characterize and discriminate effects of compounds on cells in a time-dependent and label-free manner. The presented impedance assay could be used to further characterize toxicities observed in vivo or in vitro. Due to the ease of performance it may also be a suitable screening tool.

A nine-gene signature predicting clinical outcome in cutaneous melanoma.

PURPOSE: Current histopathological staging of cutaneous melanoma is limited in predicting outcome, and complementary molecular markers are not available for prognostic assessment. The purpose of this study was to identify a quantitative gene expression score in primary melanoma and adjacent stroma that can be used in clinical routine to define, at the time of diagnosis, patient risk and need for therapy. METHODS: Expression of 92 candidate genes was quantified by RT-PCR in a training subset of 38 fresh-frozen melanomas. Correlation of gene expression with overall survival (OS) was evaluated using univariate regression analysis. Expression analysis of 11 prognostically significant genes in the complete training cohort of 91 melanomas yielded nine genes predicting outcome. Results were confirmed in a validation cohort of 44 melanomas. RESULTS: We identified a nine-gene signature associated with OS and distant metastasis-free survival. The signature comprised risk and protective genes and was applicable to melanoma samples across all AJCC stages in the presence of adjacent stroma. A signature-based risk score predicted OS in both the training cohort (multivariate regression analysis: p = 0.0004, hazard ratio 3.83) and the validation cohort, independently of AJCC staging. Consequently, when combining risk score and AJCC staging, patients in the AJCC intermediate-risk stages, IIA/B or IIIA, were re-classified either to low or high risk. CONCLUSIONS: Our gene score defines patient risk and need for therapy in melanoma. The score has the potential to be utilized in clinical routine, since it is quantitative, robust, simple, and independent of AJCC stage and sample purity.

Numerical modeling of the sensitivity of x-ray driven implosions to low-mode flux asymmetries.

The sensitivity of inertial confinement fusion implosions, of the type performed on the National Ignition Facility (NIF) [1], to low-mode flux asymmetries is investigated numerically. It is shown that large-amplitude, low-order mode shapes (Legendre polynomial P(4), resulting from low-order flux asymmetries, cause spatial variations in capsule and fuel momentum that prevent the deuterium and tritium (DT) "ice" layer from being decelerated uniformly by the hot spot pressure. This reduces the transfer of implosion kinetic energy to internal energy of the central hot spot, thus reducing the neutron yield. Furthermore, synthetic gated x-ray images of the hot spot self-emission indicate that P(4) shapes may be unquantifiable for DT layered capsules. Instead the positive P(4) asymmetry "aliases" itself as an oblate P(2) in the x-ray images. Correction of this apparent P(2) distortion can further distort the implosion while creating a round x-ray image. Long wavelength asymmetries may be playing a significant role in the observed yield reduction of NIF DT implosions relative to detailed postshot two-dimensional simulations.

Imaging of high-energy x-ray emission from cryogenic thermonuclear fuel implosions on the NIF.

Accurately assessing and optimizing the implosion performance of inertial confinement fusion capsules is a crucial step to achieving ignition on the NIF. We have applied differential filtering (matched Ross filter pairs) to provide broadband time-integrated absolute x-ray self-emission images of the imploded core of cryogenic layered implosions. This diagnostic measures the temperature- and density-sensitive bremsstrahlung emission and provides estimates of hot spot mass, mix mass, and pressure.

Measurement of electron temperature of imploded capsules at the National Ignition Facility.

The electron and ion temperatures of the imploded core plasma are two of the most important metrics of inertial confinement fusion experiments. We have developed a technique for inferring electron temperatures from the contrast of x-ray images observed through a group of x-ray filters. Generally, the plasma electron temperature exhibits spatial and temporal variations, so time-averaged and time-resolved measurements are expected to yield somewhat different results. By analyzing the intensity of images observed with both a time-integrated detector (imaging plates) and a time-resolved detector (gated micro-channel plate), we found the electron temperature observed from x-ray images to be systematically higher than the ion temperature inferred from fusion neutron spectroscopy.

Soft x-ray images of the laser entrance hole of ignition hohlraums.

Hohlraums are employed at the national ignition facility to convert laser energy into a thermal x-radiation drive, which implodes a fusion capsule, thus compressing the fuel. The x-radiation drive is measured with a low spectral resolution, time-resolved x-ray spectrometer, which views the region around the hohlraum's laser entrance hole. This measurement has no spatial resolution. To convert this to the drive inside the hohlraum, the size of the hohlraum's opening ("clear aperture") and fraction of the measured x-radiation, which comes from this opening, must be known. The size of the clear aperture is measured with the time integrated static x-ray imager (SXI). A soft x-ray imaging channel has been added to the SXI to measure the fraction of x-radiation emitted from inside the clear aperture. A multilayer mirror plus filter selects an x-ray band centered at 870 eV, near the peak of the x-ray spectrum of a 300 eV blackbody. Results from this channel and corrections to the x-radiation drive are discussed.

Direct measurement of energetic electrons coupling to an imploding low-adiabat inertial confinement fusion capsule.

We have imaged hard x-ray (>100 keV) bremsstrahlung emission from energetic electrons slowing in a plastic ablator shell during indirectly driven implosions at the National Ignition Facility. We measure 570 J in electrons with E>100 keV impinging on the fusion capsule under ignition drive conditions. This translates into an acceptable increase in the adiabat α, defined as the ratio of total deuterium-tritium fuel pressure to Fermi pressure, of 3.5%. The hard x-ray observables are consistent with detailed radiative-hydrodynamics simulations, including the sourcing and transport of these high energy electrons.

Amplification of light in a plasma by stimulated ion acoustic waves driven by multiple crossing pump beams.

Experiments demonstrate the amplification of 351 nm laser light in a hot dense plasma similar to those in inertial confinement fusion ignition experiments. A seed beam interacts with one or two counter-propagating pump beams, each with an intensity of 1.2×10(15) W/cm2 at 351 nm, crossing the seed at 24.8° at the position where the flow is Mach 1, allowing resonant stimulation of ion acoustic waves. Results show that the energy and power transferred to the seed are increased with two pumps beyond the level that occurs with a single pump, demonstrating that, under conditions similar to ignition experiments where each beam has a low gain exponent, the total scatter produced by the multiple beams can be significantly larger than that of the individual beams. It is further demonstrated that the amplification is greatly reduced when the pump polarization is orthogonal to the seed, as expected from models of stimulated scatter.

Three-wavelength scheme to optimize hohlraum coupling on the National Ignition Facility.

By using three tunable wavelengths on different cones of laser beams on the National Ignition Facility, numerical simulations show that the energy transfer between beams can be tuned to redistribute the energy within the cones of beams most prone to backscatter instabilities. These radiative hydrodynamics and laser-plasma interaction simulations have been tested against large-scale hohlraum experiments with two tunable wavelengths and reproduce the hohlraum energetics and symmetry. Using a third wavelength provides a greater level of control of the laser energy distribution and coupling in the hohlraum, and could significantly reduce stimulated Raman scattering losses and increase the hohlraum radiation drive while maintaining a good implosion symmetry.

Genetic analysis of post-mating reproductive barriers in hybridizing European Populus species.

Molecular genetic analyses of experimental crosses provide important information on the strength and nature of post-mating barriers to gene exchange between divergent populations, which are topics of great interest to evolutionary geneticists and breeders. Although not a trivial task in long-lived organisms such as trees, experimental interspecific recombinants can sometimes be created through controlled crosses involving natural F(1)'s. Here, we used this approach to understand the genetics of post-mating isolation and barriers to introgression in Populus alba and Populus tremula, two ecologically divergent, hybridizing forest trees. We studied 86 interspecific backcross (BC(1)) progeny and >350 individuals from natural populations of these species for up to 98 nuclear genetic markers, including microsatellites, indels and single nucleotide polymorphisms, and inferred the origin of the cytoplasm of the cross with plastid DNA. Genetic analysis of the BC(1) revealed extensive segregation distortions on six chromosomes, and >90% of these (12 out of 13) favored P. tremula donor alleles in the heterospecific genomic background. Since selection was documented during early diploid stages of the progeny, this surprising result was attributed to epistasis, cyto-nuclear coadaptation, heterozygote advantage at nuclear loci experiencing introgression or a combination of these. Our results indicate that gene flow across 'porous' species barriers affects these poplars and aspens beyond neutral, Mendelian expectations and suggests the mechanisms responsible. Contrary to expectations, the Populus sex determination region is not protected from introgression. Understanding the population dynamics of the Populus sex determination region will require tests based on natural interspecific hybrid zones.

Observation of high soft x-ray drive in large-scale hohlraums at the National Ignition Facility.

The first soft x-ray radiation flux measurements from hohlraums using both a 96 and a 192 beam configuration at the National Ignition Facility have shown high x-ray conversion efficiencies of ∼85%-90%. These experiments employed gold vacuum hohlraums, 6.4 mm long and 3.55 mm in diameter, heated with laser energies between 150-635 kJ. The hohlraums reached radiation temperatures of up to 340 eV. These hohlraums for the first time reached coronal plasma conditions sufficient for two-electron processes and coronal heat conduction to be important for determining the radiation drive.