Extreme ultraviolet light from a tin plasma driven by a 2-µm-wavelength laser.

An experimental study of laser-produced plasmas is performed by irradiating a planar tin target by laser pulses, of 4.8 ns duration, produced from a KTP-based 2-µm-wavelength master oscillator power amplifier. Comparative spectroscopic investigations are performed for plasmas driven by 1-µm- and 2-µm-wavelength pulsed lasers, over a wide range of laser intensities spanning 0.5 - 5 × 1011 W/cm 2. Similar extreme ultraviolet (EUV) spectra in the 5.5-25.5 nm wavelength range and underlying plasma ionicities are obtained when the intensity ratio is kept fixed at I1µm/I2µm = 2.4(7). Crucially, the conversion efficiency (CE) of 2-µm-laser energy into radiation within a 2% bandwidth centered at 13.5 nm relevant for industrial applications is found to be a factor of two larger, at a 60 degree observation angle, than in the case of the denser 1-µm-laser-driven plasma. Our findings regarding the scaling of the optimum laser intensity for efficient EUV generation and CE with drive laser wavelength are extended to other laser wavelengths using available literature data.

Extreme ultraviolet lensless imaging without object support through rotational diversity in diffractive shearing interferometry.

We report on a method that allows microscopic image reconstruction from extreme-ultraviolet diffraction patterns without the need for object support constraints or other prior knowledge about the object structure. This is achieved by introducing additional diversity through rotation of an object in a rotationally asymmetric probe beam, produced by the spatial interference between two phase-coherent high-harmonic beams. With this rotational diffractive shearing interferometry method, we demonstrate robust image reconstruction of microscopic objects at wavelengths around 30 nm, using images recorded at only three to five different object rotations.

Phase retrieval algorithms for lensless imaging using diffractive shearing interferometry.

Diffractive shearing interferometry (DSI) is a method that has recently been developed to perform lensless imaging using extreme ultraviolet radiation generated by high-harmonic generation. In this paper, we investigate the uniqueness of the DSI solution and the requirements for the support constraint size. We find that there can be multiple solutions to the DSI problem that consist of displaced copies of the actual object. These alternative solutions can be eliminated by enforcing a sufficiently tight support constraint, or by introducing additional synthetic constraints. We furthermore propose a new DSI algorithm inspired by the analogy with coherent diffractive imaging (CDI) algorithms: the original DSI algorithm is in a way analogous to the hybrid input-output algorithm as used in CDI, and we propose a new algorithm that is more analogous to the error reduction algorithm as used in CDI. We find that the newly proposed algorithm is suitable for final refinement of the reconstruction.

Broadband extreme ultraviolet dispersion measurements using a high-harmonic source.

We demonstrate direct dispersion measurements of various thin films at extreme ultraviolet (EUV) wavelengths, using a table-top laser-driven high-harmonic generation (HHG) source. In this method, spatially separated identical EUV pulses are generated through HHG with a pair of phase-locked infrared pulses. The EUV pulses are re-imaged to a sample plane using a single toroidal mirror, such that one pulse illuminates the target thin film, while the other pulse passes through a reference aperture. By comparing the EUV interference with and without a sample, we are able to extract the dispersion properties of the sample, integrated over the full film thickness. We have measured thin films of titanium, nickel, copper, and silicon nitride, demonstrating that this technique can be applied to a wide range of materials, only requiring a film thin, enough for sufficient EUV transmission.

Establishing a model of primary bovine hepatocytes with responsive growth hormone receptor expression.

The liver becomes resistant to growth hormone before parturition in dairy cows (uncoupling of the somatotropic axis). However, the mechanism of growth hormone insensitivity has not been fully described. The aim of the present study was to improve a previous model of adult bovine hepatocytes in a sandwich culture system to ensure growth hormone receptor (GHR) expression. First, we modified the protocol for hepatocyte retrieval and tested the effect of short (18 min) and long (up to 30 min) warm ischemia on hepatocyte viability. Second, we used medium additives that affect GHR expression in vivo-insulin (INS), dexamethasone (DEX), both (INS+DEX), or no hormone additives (CTRL)-to ensure the functionality of hepatocytes, as measured by lactate dehydrogenase activity and urea concentration in the medium. We also used reverse transcriptase PCR of hepatocytes to evaluate expression of albumin (ALB), hepatocyte nuclear factor 4α (HNF4A), nuclear factor-κ-B-inhibitor α (NFKBIA), cytosolic phosphoenolpyruvate carboxykinase (PCK1), and vimentin (VIM) mRNA. Moreover, we analyzed the expression of GHRtot (GHR), GHR1A, insulin-like growth factor-1 (IGF1), and IGF binding protein-2 (IGFBP2) in response to exposure to media with the different compositions. Modification of the protocol (changes in rinsing and perfusion times, buffer composition, and the volume and standardization of collagenase) led to increased cell counts and cell viability. Short warm ischemia with the modified protocol significantly increased cell count (4.7 × 107 ± 1.9 × 107 vs. 3.5 × 106 ± 1.5 × 106 vital cells/g of liver) and viability (79.1 ± 8.4 vs. 37.1 ± 8.9%). Therefore, we gathered hepatocytes from the liver after short warm ischemia with the modified protocol. For these hepatocytes, lactate dehydrogenase activity was lower in media with INS and with DEX than in media with INS+DEX or CTRL; urea concentrations were highest at d 4 for INS+DEX. As well, HNF4A and ALB were more highly expressed in hepatocytes cultured with INS and INS+DEX than in those cultured with DEX or CTRL, and the substitution of DEX suppressed VIM and NFKBIA expression but increased PCK1 expression. The expression of GHR, GHR1A, and IGF1 was suppressed by dexamethasone (DEX and INS+DEX), whereas INS distinctly increased GHR, GHR1A, and IGF1 mRNA expression. Hepatocytes in a sandwich culture showed influenceable GHR expression; this study provides a model that can be used in studies examining factors that influence the expression and signal transduction of GHR in dairy cows.

Detection of periodic structures through opaque metal layers by optical measurements of ultrafast electron dynamics.

We report on femtosecond optical pump-probe measurements of ultrafast electron dynamics to detect the presence of gratings buried underneath optically opaque gold layers. Electron energy diffusion and cooling are found to be strongly affected by the presence and type of metal buried below the gold layer. As a result, the spatially periodic buried grating is encoded on the electron temperature near the top surface, leading to a spatially periodic modulation of the optical properties near the gold surface from which a delayed probe pulse can be diffracted. Our measurements show that these effects may be useful for optical detection and alignment applications in semiconductor device manufacturing.

Diffractive shear interferometry for extreme ultraviolet high-resolution lensless imaging.

We demonstrate a novel imaging approach and associated reconstruction algorithm for far-field coherent diffractive imaging, based on the measurement of a pair of laterally sheared diffraction patterns. The differential phase profile retrieved from such a measurement leads to improved reconstruction accuracy, increased robustness against noise, and faster convergence compared to traditional coherent diffractive imaging methods. We measure laterally sheared diffraction patterns using Fourier-transform spectroscopy with two phase-locked pulse pairs from a high-harmonic source. Using this approach, we demonstrate spectrally resolved imaging at extreme ultraviolet wavelengths between 28 and 35 nm.

Spectrally resolved single-shot wavefront sensing of broadband high-harmonic sources.

Wavefront sensors are an important tool to characterize coherent beams of extreme ultraviolet radiation. However, conventional Hartmann-type sensors do not allow for independent wavefront characterization of different spectral components that may be present in a beam, which limits their applicability for intrinsically broadband high-harmonic generation (HHG) sources. Here we introduce a wavefront sensor that measures the wavefronts of all the harmonics in a HHG beam in a single camera exposure. By replacing the mask apertures with transmission gratings at different orientations, we simultaneously detect harmonic wavefronts and spectra, and obtain sensitivity to spatiotemporal structure such as pulse front tilt as well. We demonstrate the capabilities of the sensor through a parallel measurement of the wavefronts of 9 harmonics in a wavelength range between 25 and 49 nm, with up to λ/32 precision.

High-energy Nd:YAG laser system with arbitrary sub-nanosecond pulse shaping capability.

We report on a laser system capable of generating high-energy (>270 mJ) temporally shaped pulses at 1064 nm with 0.43-ns shaping resolution. The pulses are generated by modulation of a continuous-wave seed laser and subsequent amplification by a dual-stage grazing-incidence Nd:YVO4 "bounce" amplifier and a Nd:YAG power amplifier (all quasi-continuous diode-pumped). The system produces pulses with a high-quality top-hat spatial beam profile with up to 0.6 GW of peak power and 44 W of average power, a power stability of 0.22% rms, and fully programmable complex temporal shapes.

Illustrating the formation of metal nanoparticles with a growth concept based on colloidal stability.

A large number of scientific contributions is dedicated to syntheses, characterization and applications of metal nanoparticles. In contrast, only few studies on their formation mechanisms have been reported. In general, concepts to describe particle growth processes are rare. Commonly used models are not able to explain the influences of reaction parameters on the growth and the final particle size. In this contribution it is shown how the growth of colloidal metal nanoparticles can be illustrated using an approach based on colloidal stability. In the first part, investigations of various syntheses of colloidal nanoparticles (including Rh, Pd, Pt, Cu, Ag and Au) show that growth due to aggregation and coalescence is the governing principle of nanoparticle formation if the monomer supply is faster than the actual growth. In the second part of this contribution, the influences of various parameters on the growth of Au nanoparticles are studied and it is demonstrated how the colloidal stability approach can illustrate the impact of synthesis parameters on the final particle size.

Everolimus is associated with a reduced incidence of cytomegalovirus infection following de novo cardiac transplantation.

BACKGROUND: Cytomegalovirus (CMV) causes several complications following cardiac transplantation including cardiac allograft vasculopathy. Previous studies suggested that immunosuppressive treatment based on everolimus might reduce CMV infection. Aiming to better characterize the action of everolimus on CMV and its interplay with patient/recipient serology and anti-CMV prophylaxis, we analyzed data from 3 large randomized studies comparing various everolimus regimens with azathioprine (AZA)- and mycophenolate mofetil (MMF)-based regimens. METHODS: CMV data were analyzed from 1009 patients in 3 trials of de novo cardiac transplant recipients who were randomized to everolimus 1.5 mg/day, everolimus 3 mg/day, or AZA 1-3 mg/kg/day, plus standard-dose (SD) cyclosporine (CsA; study B253, n = 634); everolimus 1.5 mg/day plus SD- or reduced-dose (RD)-CsA (study A2403, n = 199); and everolimus 1.5 mg/day plus RD-CsA or MMF plus SD-CsA (study A2411, n = 176). RESULTS: In study B253, patients allocated to everolimus experienced almost a 70% reduction in odds of experiencing CMV infection compared with AZA (P < 0.001). In study A2403, CMV infection was low in both everolimus arms, irrespective of CsA dosing, and in study A2411, patients allocated to everolimus experienced an 80% reduction in odds of experiencing CMV infection, compared with MMF (P < 0.001). CMV syndrome/disease was rare and less frequent in everolimus-treated patients. Subgroup analyses showed that the benefit everolimus provides, in terms of CMV events, is retained in CMV-naïve recipients and is independent of anti-CMV prophylaxis or preemptive approaches. CONCLUSIONS: Everolimus is associated with a lower incidence of CMV infection compared with AZA and MMF, which combined with its immunosuppressive efficacy and antiproliferative effects may positively impact long-term outcomes.

Optimizing pump-probe reflectivity measurements of ultrafast photoacoustics with modulated asynchronous optical sampling.

Time-resolved optical pump-probe experiments enable the study of complex light-matter interactions on ultrafast timescales, provided that they reach sufficient sensitivity. For instance, with pump-induced ultrafast photoacoustics, probing the typically small changes in optical properties requires a high signal-to-noise ratio. Asynchronous optical sampling (ASOPS), using two separate pulsed lasers at slightly different repetition rates, can be effective at removing noise by averaging many rapidly acquired traces. However, the pump-probe delay scan with ASOPS is always as long as the pump pulse interval, which is inefficient if the delay-time range of interest is shorter. Here, we demonstrate two modified ASOPS schemes that optimize measurement efficiency by only scanning the range of interest. The modification based on frequency modulated ASOPS (MASOPS) is most efficient, especially in the presence of low-frequency flicker noise. We provide a proof-of-concept measurement of ultrafast photoacoustics in which we use MASOPS to scan a time delay of 1/20 of the pump pulse interval. The resulting noise floor is 20 times lower compared to conventional ASOPS, allowing for 20 times faster measurements. Furthermore, we show that by taking experimental noise characteristics into account, more traditional pump-probe methods can also be optimized.

Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial.

In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients.

Sotrastaurin, a selective protein-kinase-C inhibitor, blocks early T-cell activation through a calcineurin-independent mechanism. In this study, de novo renal transplant recipients with immediate graft function were randomized 1:2 to tacrolimus (control, n = 44) or sotrastaurin (300 mg b.i.d.; n = 81). All patients received basiliximab, mycophenolic acid (MPA) and steroids. The primary endpoint was the composite of treated biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up at month 3. The main safety assessment was estimated glomerular filtration rate (eGFR); modification of diet in renal disease (MDRD) at month 3. Composite efficacy failure at month 3 was higher for the sotrastaurin versus control regimen (25.7% vs. 4.5%, p = 0.001), driven by higher BPAR rates (23.6% vs. 4.5%, p = 0.003), which led to early study termination. Median (± standard deviation [SD]) eGFR was higher for sotrastaurin versus control at all timepoints from day 7 (month 3: 59.0 ± 22.3 vs. 49.5 ± 17.7 mL/min/1.73 m(2) , p = 0.006). The most common adverse events were gastrointestinal disorders (control: 63.6%; sotrastaurin: 88.9%) which led to study-medication discontinuation in two sotrastaurin patients. This study demonstrated a lower degree of efficacy but better renal function with the calcineurin-inhibitor-free regimen of sotrastaurin+MPA versus the tacrolimus-based control. Ongoing studies are evaluating alternative sotrastaurin regimens.

Association of owner-reported noise with findings during dynamic respiratory endoscopy in Thoroughbred racehorses.

REASONS FOR PERFORMING STUDY: To determine the association between owner-reported noise and findings during dynamic respiratory endoscopy (DRE) in a large case series. HYPOTHESIS: The sensitivity of owner-reported noise for dynamic upper respiratory tract obstructions in horses is low, and the specificity is high. METHODS: One hundred horses underwent DRE for the investigation of abnormal respiratory noise and/or poor performance. The association of abnormal noise with findings during DRE was evaluated. RESULTS: Eighty-five horses underwent DRE for the investigation of abnormal respiratory noise. Of these, 82% were found to have one or more obstructive upper respiratory tract abnormalities during DRE. Forty-eight percent of horses reported to gurgle, rattle or make a rough noise were diagnosed with solitary palatal dysfunction. A further 24% with this history showed palatal dysfunction in combination with an additional abnormality. Twenty-seven percent of horses with a history of whistling or roaring showed some degree of recurrent laryngeal neuropathy. Seven percent of horses with a history of whistling or roaring had vocal cord collapse as a solitary condition, whereas 40% had vocal cord collapse and another abnormality. The sensitivity of abnormal respiratory noise for any obstruction of the upper portion of the respiratory tract was high (84%), while the specificity was low (25%). Characteristic owner reported noise patterns showed moderate to low sensitivity for specific conditions. Whistling and roaring showed the highest specificity (≥80%) for laryngeal dysfunction. CONCLUSION: Diagnosis of upper respiratory tract obstructions based solely on owner-reported noise and performance history may result in incomplete diagnoses. CLINICAL RELEVANCE: DRE should be performed in horses with abnormal respiratory noise to rule out complex conditions of the upper portion of the respiratory tract.

Prominent radiative contributions from multiply-excited states in laser-produced tin plasma for nanolithography.

Extreme ultraviolet (EUV) lithography is currently entering high-volume manufacturing to enable the continued miniaturization of semiconductor devices. The required EUV light, at 13.5 nm wavelength, is produced in a hot and dense laser-driven tin plasma. The atomic origins of this light are demonstrably poorly understood. Here we calculate detailed tin opacity spectra using the Los Alamos atomic physics suite ATOMIC and validate these calculations with experimental comparisons. Our key finding is that EUV light largely originates from transitions between multiply-excited states, and not from the singly-excited states decaying to the ground state as is the current paradigm. Moreover, we find that transitions between these multiply-excited states also contribute in the same narrow window around 13.5 nm as those originating from singly-excited states, and this striking property holds over a wide range of charge states. We thus reveal the doubly magic behavior of tin and the origins of the EUV light.

Single-shot two-dimensional full-range optical coherence tomography achieved by dispersion control.

We present a full-range Fourier-domain optical coherence tomography (OCT) system that is capable of acquiring two-dimensional images of living tissue in a single shot. By using line illumination of the sample in combination with a two-dimensional imaging spectrometer, 1040 depth scans are performed simultaneously on a sub-millisecond timescale. Furthermore, we demonstrate an easy and flexible real-time single-shot technique for full-range (complex-conjugate cancelled) OCT imaging that is compatible with both two-dimensional as well as ultrahigh-resolution OCT. By implementing a dispersion imbalance between reference and sample arms of the interferometer, we eliminate the complex-conjugate signal through numerical dispersion compensation, effectively increasing the useful depth range by a factor of two. The system allows us to record 6.7 x 3.2 mm images at 5 microm depth resolution in 0.2 ms. Data postprocessing requires only 4 s. We demonstrate the capability of our system by imaging the anterior chamber of a mouse eye in vitro, as well as human skin in vivo.

A regression model applied to gender-specific ethanol elimination rates from blood and breath measurements in non-alcoholics.

As elimination rates for alcohol are suggested to be gender specific, a novel regression model has been applied to estimate these rates for both men and women using experimentally measured data from 81 female and 96 male volunteers described in previous papers. Breath alcohol measurements were done with the Alcotest 7110 Evidential device and were coupled with concomitant sampling of venous blood. Statistical analyses involved use of a mixed linear model for blood alcohol concentration (BAC) and breath alcohol concentration (BrAC), respectively. The model takes regression lines for each test subject into account with an individual starting value (2 h after the end of drinking) and with an individual alcohol elimination rate per hour (coincidental effects). Further, the data was modeled so that an average alcohol elimination rate per hour could be estimated separately for both genders (constant effects). This enables us to methodically correctly estimate the back calculation. The elimination rates beta (60), which can be used for minimum and maximum back calculations for the BAC, were 0.115 g/kg/h and 0.260 g/kg/h, respectively, for women and 0.096 g/kg/h and 0.241 g/kg/h, respectively, for men. These figures widely deviate from gender-unspecific values commonly used in Germany (0.1 and 0.2 g/kg/h, respectively). The corresponding values for the BrAC were 0.061 mg/l/h and 0.124 mg/l/h for women and 0.049 mg/l/h and 0.112 mg/l/h for men. The probability of an over- or underestimation of the abovementioned extreme values is 0.3% in each case.

Safety and tolerability of pardoprunox, a new partial dopamine agonist, in a randomized, controlled study of patients with advanced Parkinson's disease.

AIMS: To investigate the safety and tolerability of pardoprunox (SLV308), a novel partial dopamine agonist, as an adjunct to levodopa in patients with advanced Parkinson's disease, using two titration schedules. METHODS: Patients were randomized to pardoprunox (n = 51) or placebo (n = 11). Pardoprunox was titrated to the highest tolerated dose (range, 0.3-42 mg/day) over 7 weeks, using a gradual dose escalation without intermediate steps (group 1) or with intermediate steps (group 2). RESULTS: The cumulative drop-out rate was greater in group 1 (without intermediate steps, 56.0%) than in group 2 (with intermediate steps, 34.6%), or with placebo (9.1%). In group 2, doses up to 18 mg/day were well tolerated with a cumulative drop-out rate of 7.7% (2/26) and a drop-out rate due to adverse events of 4.0% (1/26). The most common adverse events reported were nausea, vomiting, headache, and dizziness. There was a trend for reduced OFF time (p = 0.054) in the combined pardoprunox group compared to placebo. CONCLUSIONS: The pardoprunox safety and tolerability profile as an adjunct to levodopa was improved using a gradual titration schedule that included intermediate dose steps. Using this titration, doses up to 18 mg/day were well tolerated.

Ultrafast double-pulse parametric amplification for precision Ramsey metrology.

We demonstrate phase stable, mJ-level parametric amplification of pulse pairs originating from a Ti:Sapphire frequency comb laser. The amplifier-induced phase shift between the pulses has been determined interferometrically with an accuracy of approximately 10 mrad. Typical phase shifts are on the order of 50-200 mrad, depending on the operating conditions. The measured phase-relation can be as stable as 20 mrad rms (1/300(th) of an optical cycle). This makes the system suitable for Ramsey spectroscopy at short wavelengths by employing harmonic upconversion of the double-pulses in nonlinear media.