Influence of Selective Carbon 1s Excitation on Auger-Meitner Decay in the ESCA Molecule.

Two-dimensional spectral mapping is used to visualize how resonant Auger-Meitner spectra are influenced by the site of the initial core-electron excitation and the symmetry of the core-excited state in the trifluoroethyl acetate molecule (ESCA). We observe a significant enhancement of electron yield for excitation of the COO 1s → π* and CF3 1s → σ* resonances unlike excitation at resonances involving the CH3 and CH2 sites. The CF3 1s → π* and CF3 1s → σ* resonance spectra are very different from each other, with the latter populating most valence states equally. Two complementary electronic structure calculations for the photoelectron cross section and Auger-Meitner intensity are shown to effectively reproduce the site- and state-selective nature of the resonant enhancement features. The site of the core-electron excitation and the respective final state hole locality increase the sensistivity of the photoelectron signal at specific functional group sites. This showcases resonant Auger-Meitner decay as a potentially powerful tool for selectively probing structural changes at specific functional group sites of polyatomic molecules.

Pulse Energy and Pulse Duration Effects in the Ionization and Fragmentation of Iodomethane by Ultraintense Hard X Rays.

The interaction of intense femtosecond x-ray pulses with molecules sensitively depends on the interplay between multiple photoabsorptions, Auger decay, charge rearrangement, and nuclear motion. Here, we report on a combined experimental and theoretical study of the ionization and fragmentation of iodomethane (CH_{3}I) by ultraintense (∼10^{19} W/cm^{2}) x-ray pulses at 8.3 keV, demonstrating how these dynamics depend on the x-ray pulse energy and duration. We show that the timing of multiple ionization steps leading to a particular reaction product and, thus, the product's final kinetic energy, is determined by the pulse duration rather than the pulse energy or intensity. While the overall degree of ionization is mainly defined by the pulse energy, our measurement reveals that the yield of the fragments with the highest charge states is enhanced for short pulse durations, in contrast to earlier observations for atoms and small molecules in the soft x-ray domain. We attribute this effect to a decreased charge transfer efficiency at larger internuclear separations, which are reached during longer pulses.

Resonant Inelastic X-Ray Scattering Reveals Hidden Local Transitions of the Aqueous OH Radical.

Resonant inelastic x-ray scattering (RIXS) provides remarkable opportunities to interrogate ultrafast dynamics in liquids. Here we use RIXS to study the fundamentally and practically important hydroxyl radical in liquid water, OH(aq). Impulsive ionization of pure liquid water produced a short-lived population of OH(aq), which was probed using femtosecond x-rays from an x-ray free-electron laser. We find that RIXS reveals localized electronic transitions that are masked in the ultraviolet absorption spectrum by strong charge-transfer transitions-thus providing a means to investigate the evolving electronic structure and reactivity of the hydroxyl radical in aqueous and heterogeneous environments. First-principles calculations provide interpretation of the main spectral features.

Observation of the fastest chemical processes in the radiolysis of water.

Elementary processes associated with ionization of liquid water provide a framework for understanding radiation-matter interactions in chemistry and biology. Although numerous studies have been conducted on the dynamics of the hydrated electron, its partner arising from ionization of liquid water, H2O+, remains elusive. We used tunable femtosecond soft x-ray pulses from an x-ray free electron laser to reveal the dynamics of the valence hole created by strong-field ionization and to track the primary proton transfer reaction giving rise to the formation of OH. The isolated resonance associated with the valence hole (H2O+/OH) enabled straightforward detection. Molecular dynamics simulations revealed that the x-ray spectra are sensitive to structural dynamics at the ionization site. We found signatures of hydrated-electron dynamics in the x-ray spectrum.

Femtosecond response of polyatomic molecules to ultra-intense hard X-rays.

X-ray free-electron lasers enable the investigation of the structure and dynamics of diverse systems, including atoms, molecules, nanocrystals and single bioparticles, under extreme conditions. Many imaging applications that target biological systems and complex materials use hard X-ray pulses with extremely high peak intensities (exceeding 1020 watts per square centimetre). However, fundamental investigations have focused mainly on the individual response of atoms and small molecules using soft X-rays with much lower intensities. Studies with intense X-ray pulses have shown that irradiated atoms reach a very high degree of ionization, owing to multiphoton absorption, which in a heteronuclear molecular system occurs predominantly locally on a heavy atom (provided that the absorption cross-section of the heavy atom is considerably larger than those of its neighbours) and is followed by efficient redistribution of the induced charge. In serial femtosecond crystallography of biological objects-an application of X-ray free-electron lasers that greatly enhances our ability to determine protein structure-the ionization of heavy atoms increases the local radiation damage that is seen in the diffraction patterns of these objects and has been suggested as a way of phasing the diffraction data. On the basis of experiments using either soft or less-intense hard X-rays, it is thought that the induced charge and associated radiation damage of atoms in polyatomic molecules can be inferred from the charge that is induced in an isolated atom under otherwise comparable irradiation conditions. Here we show that the femtosecond response of small polyatomic molecules that contain one heavy atom to ultra-intense (with intensities approaching 1020 watts per square centimetre), hard (with photon energies of 8.3 kiloelectronvolts) X-ray pulses is qualitatively different: our experimental and modelling results establish that, under these conditions, the ionization of a molecule is considerably enhanced compared to that of an individual heavy atom with the same absorption cross-section. This enhancement is driven by ultrafast charge transfer within the molecule, which refills the core holes that are created in the heavy atom, providing further targets for inner-shell ionization and resulting in the emission of more than 50 electrons during the X-ray pulse. Our results demonstrate that efficient modelling of X-ray-driven processes in complex systems at ultrahigh intensities is feasible.

Hetero-site-specific X-ray pump-probe spectroscopy for femtosecond intramolecular dynamics.

New capabilities at X-ray free-electron laser facilities allow the generation of two-colour femtosecond X-ray pulses, opening the possibility of performing ultrafast studies of X-ray-induced phenomena. Particularly, the experimental realization of hetero-site-specific X-ray-pump/X-ray-probe spectroscopy is of special interest, in which an X-ray pump pulse is absorbed at one site within a molecule and an X-ray probe pulse follows the X-ray-induced dynamics at another site within the same molecule. Here we show experimental evidence of a hetero-site pump-probe signal. By using two-colour 10-fs X-ray pulses, we are able to observe the femtosecond time dependence for the formation of F ions during the fragmentation of XeF2 molecules following X-ray absorption at the Xe site.

Solvation dynamics monitored by combined X-ray spectroscopies and scattering: photoinduced spin transition in aqueous [Fe(bpy)3](2+).

We have studied the photoinduced low spin (LS) to high spin (HS) conversion of aqueous Fe(bpy)3 with pulse-limited time resolution. In a combined setup permitting simultaneous X-ray diffuse scattering (XDS) and spectroscopic measurements at a MHz repetition rate we have unraveled the interplay between intramolecular dynamics and the intermolecular caging solvent response with 100 ps time resolution. On this time scale the ultrafast spin transition including intramolecular geometric structure changes as well as the concomitant bulk solvent heating process due to energy dissipation from the excited HS molecule are long completed. The heating is nevertheless observed to further increase due to the excess energy between HS and LS states released on a subnanosecond time scale. The analysis of the spectroscopic data allows precise determination of the excited population which efficiently reduces the number of free parameters in the XDS analysis, and both combined permit extraction of information about the structural dynamics of the first solvation shell.

The effects of nonsteroidal anti-inflammatory drugs on clinical outcomes, synovial fluid cytokine concentration and signal transduction pathways in knee osteoarthritis. A randomized open label trial.

OBJECTIVE: We investigated the effects of celecoxib, diclofenac, and ibuprofen on the disease-specific quality of life, synovial fluid cytokines and signal transduction pathways in symptomatic knee osteoarthritis (OA). DESIGN: Ninety patients scheduled for a total knee arthroplasty (TKA) were randomized to six groups that were treated with low and high dosages of celecoxib, diclofenac or ibuprofen. At the time of the first admission (T0) and at surgery (T1 = 14 days after beginning of the nonsteroidal anti-inflammatory drugs (NSAIDs)), samples of knee synovial fluid were obtained from each patient for analysis. During the surgery the synovial tissue was harvested from the knee of patients. The Western Ontario and McMaster universities (WOMAC) score was used to evaluate the patient disease-specific quality of life at T0 and T1. Microarray tests performed at T0 and T1 were used to evaluate the effects of NSAIDs on Tumor necrosis factor (TNF)-alpha, Interleukin-6 (IL-6), IL8 and Vascular endothelial growth factor (VEGF) concentration in the synovial fluid. Western blot assays evaluated the effects of NSAIDs on MAP kinase (MAPK) signal transduction pathway in the synovial membrane. RESULTS: NSAID treatment induced a statistically significant improvement in the WOMAC score and a statistically significant decrease in the IL-6, VEGF and TNF-alpha concentration in the synovial fluid. Higher dosages of NSAIDs provided a greater improvement in the disease-specific quality of life of patients and lower concentrations of pro-inflammatory cytokines in the synovial fluid. Inhibition of MAPKs was noted after NSAID treatment. CONCLUSION: Short-term NSAID treatment improves the patient disease-specific quality of life with a parallel decrease in pro-inflammatory synovial fluid cytokine levels in knee OA. Signal transduction pathways may be involved in regulating the anti-inflammatory effects of NSAIDs. ClinicalTrial.gov: NCT01860833.

Characteristics and clinical implications of the pharmacokinetic profile of ibuprofen in patients with knee osteoarthritis.

BACKGROUND AND OBJECTIVE: Ibuprofen is a non-selective cyclo-oxygenase (COX)-1/COX-2 inhibitor used to treat pain conditions and inflammation. Limited data have been published concerning the pharmacokinetic profile and clinical effects of ibuprofen in patients with osteoarthritis (OA). In this paper we compared the pharmacokinetic and clinical profile of ibuprofen (at a dosage of from 800 mg/day to 1800 mg/day) administered in patients affected by severe knee OA. METHODS: Ibuprofen was administered for 7 days to patients who were scheduled to undergo knee arthroplasty due to OA. After 7 days, the ibuprofen concentration in plasma and synovial fluid was measured through both high-performance liquid chromatography (HPLC)-UV and gas chromatography-mass spectroscopy (GC/MS), while clinical effects were evaluated through both visual analogue scale (VAS) and Western Ontario and McMaster Universities (WOMAC) scores. The Naranjo scale and the WHO causality assessment scale were used for estimating the probability of adverse drug reactions (ADRs). The severity of ADRs was assessed by the modified Hartwig and Siegel scale. RESULTS: Ibuprofen showed a dose-dependent diffusion in both plasma and synovial fluid, which was related to the reduction of pain intensity and improvement of health status, without the development of ADRs. CONCLUSION: Ibuprofen at higher dosages can be expected to provide better control of OA symptoms as a result of higher tissue distribution.

Guest-host interactions investigated by time-resolved X­ray spectroscopies and scattering at MHz rates: solvation dynamics and photoinduced spin transition in aqueous Fe(bipy)3(2+).

We have studied the photoinduced low spin (LS) to high spin (HS) conversion of [Fe(bipy)(3)](2+) in aqueous solution. In a laser pump/X-ray probe synchrotron setup permitting simultaneous, time-resolved X-ray diffuse scattering (XDS) and X-ray spectroscopic measurements at a 3.26 MHz repetition rate, we observed the interplay between intramolecular dynamics and the intermolecular caging solvent response with better than 100 ps time resolution. On this time scale, the initial ultrafast spin transition and the associated intramolecular geometric structure changes are long completed, as is the solvent heating due to the initial energy dissipation from the excited HS molecule. Combining information from X-ray emission spectroscopy and scattering, the excitation fraction as well as the temperature and density changes of the solvent can be closely followed on the subnanosecond time scale of the HS lifetime, allowing the detection of an ultrafast change in bulk solvent density. An analysis approach directly utilizing the spectroscopic data in the XDS analysis effectively reduces the number of free parameters, and both combined permit extraction of information about the ultrafast structural dynamics of the caging solvent, in particular, a decrease in the number of water molecules in the first solvation shell is inferred, as predicted by recent theoretical work.

Unveiling and driving hidden resonances with high-fluence, high-intensity x-ray pulses.

We show that high fluence, high-intensity x-ray pulses from the world's first hard x-ray free-electron laser produce nonlinear phenomena that differ dramatically from the linear x-ray-matter interaction processes that are encountered at synchrotron x-ray sources. We use intense x-ray pulses of sub-10-fs duration to first reveal and subsequently drive the 1s↔2p resonance in singly ionized neon. This photon-driven cycling of an inner-shell electron modifies the Auger decay process, as evidenced by line shape modification. Our work demonstrates the propensity of high-fluence, femtosecond x-ray pulses to alter the target within a single pulse, i.e., to unveil hidden resonances, by cracking open inner shells energetically inaccessible via single-photon absorption, and to consequently trigger damaging electron cascades at unexpectedly low photon energies.

Femtosecond electronic response of atoms to ultra-intense X-rays.

An era of exploring the interactions of high-intensity, hard X-rays with matter has begun with the start-up of a hard-X-ray free-electron laser, the Linac Coherent Light Source (LCLS). Understanding how electrons in matter respond to ultra-intense X-ray radiation is essential for all applications. Here we reveal the nature of the electronic response in a free atom to unprecedented high-intensity, short-wavelength, high-fluence radiation (respectively 10(18) W cm(-2), 1.5-0.6 nm, approximately 10(5) X-ray photons per A(2)). At this fluence, the neon target inevitably changes during the course of a single femtosecond-duration X-ray pulse-by sequentially ejecting electrons-to produce fully-stripped neon through absorption of six photons. Rapid photoejection of inner-shell electrons produces 'hollow' atoms and an intensity-induced X-ray transparency. Such transparency, due to the presence of inner-shell vacancies, can be induced in all atomic, molecular and condensed matter systems at high intensity. Quantitative comparison with theory allows us to extract LCLS fluence and pulse duration. Our successful modelling of X-ray/atom interactions using a straightforward rate equation approach augurs favourably for extension to complex systems.

Low-energy nondipole effects in molecular nitrogen valence-shell photoionization.

Observations are reported for the first time of significant nondipole effects in the photoionization of the outer-valence orbitals of diatomic molecules. Measured nondipole angular-distribution parameters for the 3sigma(g), 1pi(u), and 2sigma(u) shells of N2 exhibit spectral variations with incident photon energies from thresholds to approximately 200 eV which are attributed via concomitant calculations to particular final-state symmetry waves arising from (E1)multiply sign in circle(M1,E2) radiation-matter interactions first-order in photon momentum. Comparisons with previously reported K-edge studies in N2 verify linear scaling with photon momentum, accounting in part for the significantly enhanced nondipole behavior observed in inner-shell ionization at correspondingly higher momentum values in this molecule.

X-ray microprobe of orbital alignment in strong-field ionized atoms.

We have developed a synchrotron-based, time-resolved x-ray microprobe to investigate optical strong-field processes at intermediate intensities (10(14) - 10(15) W/cm2). This quantum-state specific probe has enabled the direct observation of orbital alignment in the residual ion produced by strong-field ionization of krypton atoms via resonant, polarized x-ray absorption. We found strong alignment to persist for a period long compared to the spin-orbit coupling time scale (6.2 fs). The observed degree of alignment can be explained by models that incorporate spin-orbit coupling. The methodology is applicable to a wide range of problems.

The Foundation Programme and the emergency department: a review of the curriculum and experience of a UK pilot.

The emergency department will have an important role within the Modernising Medical Careers Foundation Programme (FP) in the United Kingdom. Many of the key competencies required of Foundation training relate to acute medical care. However, the Foundation curriculum is a large and complex document. Some of the detail within it has particular implications for emergency medicine. Issues of curriculum content, teaching styles, and assessment have a potentially significant effect upon established working practices in a typical unit. This paper examines the FP curriculum to allow a clearer understanding of its key elements. Problems in relation to delivery of teaching and the quantity of assessment required are highlighted and solutions discussed. Experience from a UK pilot site for Foundation training in emergency medicine which began in August 2004 is used to illustrate how some of these issues have been addressed. The review concludes with a series of practical hints and tips which others may find useful as they prepare to incorporate FP trainees locally.

Dramatic nondipole effects in low-energy photoionization: experimental and theoretical study of Xe 5s.

The Xe 5s nondipole photoelectron parameter gamma is obtained experimentally and theoretically from threshold to approximately 200 eV photon energy. Significant nondipole effects are seen even in the threshold region of this valence shell photoionization. In addition, contrary to previous understanding, clear evidence of interchannel coupling among quadrupole photoionization channels is found.

Triple ionization of lithium by electron impact.

Ejection of the three electrons from lithium in a single electron collision has been observed for the first time. Triply charged lithium was observed in an ion time-of-flight spectrum following electron impact on a sample of ultracold, trapped lithium. The higher signal/background afforded by the trap environment made the observation of Li3+ possible. We measured the ratios of triple-to-double and double-to-single ionization at an impact energy of 1000 eV. The 3+/2+ ratio is approximately 0.001, a value 2 orders of magnitude lower than semiempirical predictions. We present a simple method that uses photoionization data combined with sum-rule analysis to predict the asymptotic charge-state ratios. The sum-rule predictions compare reasonably with experiment and shake calculations, but disagree sharply with the semiempirical estimates.

Photoexcitation of a dipole-forbidden resonance in helium.

We have observed photoexcitation of the dipole-forbidden 1s(2) 1S0-->2p(2) 1D2 resonance in helium by measuring the nondipolar forward-backward asymmetry of photoelectron angular distributions in the 2l2l(') autoionizing region. By exploiting the electric dipole-quadrupole interference in the excitation of both the 2s2p 1P1 and 2p(2) 1D2 levels, we have observed the quadrupole resonance in photoabsorption and extracted its Fano line shape parameters and the relative phase of the 1sEp and 1sEd continua. We find the quadrupole line profile index q(2) to be markedly different from theoretical expectations.

A study of the effects of cranial electrical stimulation on attention and concentration.

There have been several anecdotal accounts that cranial electrical stimulation (CES) enhances attention and the ability to learn new tasks in a normal population, but only one published investigation confirms that CES improves attention using the Alpha Stim CES (Madden and Kirsch, 1987). The purpose of this study was to corroborate the findings of Madden and Kirsch, using more precise measures of attention, such as a Continuous Performance Test (CPT). A pretest and posttest CPT was given to two groups using the LISS CES device. The control group consisted of twenty-one subjects who received the placebo treatment. The experimental group of thirty-one subjects received twenty minutes of CES. Four measures of the CPT show significant gains in attention: Number of Hits, p =.010 Hit RT ISI Change, p =.016, Risk Taking, p =.055; and Attentiveness, p =.054. Based on subjects who demonstrated improvement by one standard deviation on two different measures of the CPT, thirty-one percent of the experimental group improved versus four percent of the control group. The use of CES as a method of increasing attention is a promising area that requires further investigation.

Medical readiness training exercise in El Salvador, Central America, 1996.

Medical Readiness Training Exercises (MEDRETEs) can be a valuable training tool for U.S. Army personnel in remote areas of deployment. We report our experience of the MEDRETE in El Salvador in 1996. Working with foreign physicians of the host country was a positive experience in which we learned local customs and mutual cooperation. Evaluation and treatment of nearly 6,000 patients increased goodwill in the community and provided an opportunity for teamwork for Army Reserve medical units, including increased discussions of public health issues. We also report on the field applicability of the advanced laboratory and pharmacy equipment we included in our training.