Experimental capabilities for liquid jet samples at sub-MHz rates at the FXE Instrument at European XFEL.

The Femtosecond X-ray Experiments (FXE) instrument at the European X-ray Free-Electron Laser (EuXFEL) provides an optimized platform for investigations of ultrafast physical, chemical and biological processes. It operates in the energy range 4.7-20 keV accommodating flexible and versatile environments for a wide range of samples using diverse ultrafast X-ray spectroscopic, scattering and diffraction techniques. FXE is particularly suitable for experiments taking advantage of the sub-MHz repetition rates provided by the EuXFEL. In this paper a dedicated setup for studies on ultrafast biological and chemical dynamics in solution phase at sub-MHz rates at FXE is presented. Particular emphasis on the different liquid jet sample delivery options and their performance is given. Our portfolio of high-speed jets compatible with sub-MHz experiments includes cylindrical jets, gas dynamic virtual nozzles and flat jets. The capability to perform multi-color X-ray emission spectroscopy (XES) experiments is illustrated by a set of measurements using the dispersive X-ray spectrometer in von Hamos geometry. Static XES data collected using a multi-crystal scanning Johann-type spectrometer are also presented. A few examples of experimental results on ultrafast time-resolved X-ray emission spectroscopy and wide-angle X-ray scattering at sub-MHz pulse repetition rates are given.

Towards X-ray transient grating spectroscopy.

The extension of transient grating spectroscopy to the x-ray regime will create numerous opportunities, ranging from the study of thermal transport in the ballistic regime to charge, spin, and energy transfer processes with atomic spatial and femtosecond temporal resolution. Studies involving complicated split-and-delay lines have not yet been successful in achieving this goal. Here we propose a novel, simple method based on the Talbot effect for converging beams, which can easily be implemented at current x-ray free electron lasers. We validate our proposal by analyzing printed interference patterns on polymethyl methacrylate and gold samples using ∼3 keV X-ray pulses.

Short-wavelength free-electron laser sources and science: a review.

This review is focused on free-electron lasers (FELs) in the hard to soft x-ray regime. The aim is to provide newcomers to the area with insights into: the basic physics of FELs, the qualities of the radiation they produce, the challenges of transmitting that radiation to end users and the diversity of current scientific applications. Initial consideration is given to FEL theory in order to provide the foundation for discussion of FEL output properties and the technical challenges of short-wavelength FELs. This is followed by an overview of existing x-ray FEL facilities, future facilities and FEL frontiers. To provide a context for information in the above sections, a detailed comparison of the photon pulse characteristics of FEL sources with those of other sources of high brightness x-rays is made. A brief summary of FEL beamline design and photon diagnostics then precedes an overview of FEL scientific applications. Recent highlights are covered in sections on structural biology, atomic and molecular physics, photochemistry, non-linear spectroscopy, shock physics, solid density plasmas. A short industrial perspective is also included to emphasise potential in this area.

Editor's Choice - Subsequent Results for Arch Aneurysm Repair with Inner Branched Endografts.

OBJECTIVES: The aim was to evaluate the current results of aortic arch aneurysm repair using inner branched endografts performed in three high volume aortic endovascular centers and to compare them to the pioneering global experience with this technology. METHODS: Included patients underwent repair of aortic arch aneurysms >55 mm in diameter using inner branched endograft technology between April 2013 and November 2014. All patients were deemed unfit for open surgery. Inner branches were designed to perfuse the brachiocephalic trunk and the left common carotid artery in all cases. A left subclavian artery (LSA) revascularization was performed prior to the arch endovascular repair. Data were collected retrospectively in an electronic database. Parameters included length of procedure, fluoroscopy time, contrast volume, technical success, presence of endoleaks, early and late complications, and mortality. RESULTS: Twenty-seven patients were included in the study. Technical success was achieved in all cases. No patients died during the 30 day post-operative period. Early neurologic events included two major strokes (7.4%) and one minor stroke (3.7%). Transient spinal cord ischemia with full recovery was observed in two patients (7.4%). Four patients (14.8%) underwent early (<30 day) re-interventions; these were for an access complication, an ischemic limb and exploration of the left ventricle through a sternotomy in two patients. During follow up (median 12 months), one patient (3.7%) died from a remote thoraco-abdominal aneurysm rupture. There were three Type 2 endoleaks (11.1%). Two re-interventions (7.4%) were performed, one to treat a Type 2 endoleak and one to treat a septic false aneurysm. A significant decrease in overall mortality was observed when comparing patients from the early experience with patients from the current report. CONCLUSIONS: The early outcomes associated with this technology are favorable. Branched endografting of aortic arch aneurysms should be considered in patients unfit for open surgery.

X-ray spectroscopic study of solvent effects on the ferrous and ferric hexacyanide anions.

We present an Fe Kα resonant inelastic X-ray scattering (RIXS) and X-ray emission (XES) study of ferrous and ferric hexacyanide dissolved in water and ethylene glycol. We observe that transitions below the absorption edge show that the solvent has a distinct effect on the valence electronic structure. In addition, both the RIXS and XES spectra show a stabilization of the 2p levels when dissolved in water. Using molecular dynamics simulations, we propose that this effect arises from the hydrogen-bonding interactions between the complex and nearby solvent molecules. This withdraws electron density from the ligands, stabilizing the complex but also causing a slight increase in π-backbonding.

Determination of procoagulant activity in human normal immunoglobulin preparations for therapeutic use by FXIa chromogenic assay: Evaluation of test kit sensitivity, reference standard performance and product formulation effects on the FXIa assay.

In 2010, the reporting of thrombotic adverse events for one subcutaneous and certain intravenous immunoglobulins (IGs) raised some concerns. In Europe, regulatory bodies rapidly revised compendial specifications for therapeutic IGs to ensure they do not exhibit thrombogenic (procoagulant) activity (PCA). At the global level, a working group (GWG) was launched with the aim of assessing PCA measurement methods and limits, considering results obtained by human IG manufacturers during in-process controls. The GWG created three dedicated subgroups to investigate the FXIa chromogenic assay, the non-activated partial thromboplastin time (NAPTT) test and the thrombin generation assay (TGA). The European Directorate for the Quality of Medicines & HealthCare (EDQM) was responsible for co-ordinating the subgroup in charge of evaluating the FXIa chromogenic assay in a study that assessed the sensitivity and robustness of two commercial chromogenic FXIa test kits. The impact of IG product formulation on FXIa recovery and the suitability of PCA-containing IG products as potential reference standards/controls were also assessed. IG materials representative of marketed products were provided to four laboratories for a study that was carried out in two steps: 1) two chromogenic FXIa test kit manufacturers assessed the performance and determined optimal test conditions by their respective methods, 2) two OMCLs studied both kits using an optimised study design. Regarding sensitivity, the study results identified suitable dose-response intervals and limits with both chromogenic FXIa test kits. This allowed the establishment of dilution ranges for optimal detection of FXIa/PCA in 5 % and 10 % IG products in the range of 1-6 mIU/mL. However, careful optimisation of the sample dilutions was required (notably to avoid potential matrix effects) and the choice of the mode of data acquisition (kinetic or end-point method) contributed to sensitivity in routine use. Importantly, the composition of IG products was of minor concern for FXIa determination with both test kits. Potential reference materials evaluated in the study behaved as expected and could be useful should a separate reference standard to the FXIa WHO IS be deemed necessary in future.

X-ray absorption spectroscopy of ground and excited rhenium-carbonyl-diimine complexes: evidence for a two-center electron transfer.

Steady-state and picosecond time-resolved X-ray absorption spectroscopy is used to study the ground and lowest triplet states of [ReX(CO)(3)(bpy)](n+), X = Etpy (n = 1), Cl, or Br (n = 0). We demonstrate that the transient spectra at both the Re L(3)- and Br K-edges show the emergence of a pre-edge feature, absent in the ground-state spectrum, which is associated with the electron hole created in the highest occupied molecular orbital following photoexcitation. Importantly, these features have the same dynamics, confirming previous predictions that the low-lying excited states of these complexes involve a two-center charge transfer from both the Re and the ligand, X. We also demonstrate that the DFT optimized ground and excited structures allow us to reproduce the experimental XANES and EXAFS spectra. The ground-state structural refinement shows that the Br atom contributes very little to the latter, whereas the Re-C-O scattering paths are dominant due to the so-called focusing effect. For the excited-state spectrum, the Re-X bond undergoes one of the largest changes but still remains a weak contribution to the photoinduced changes of the EXAFS spectrum.

Solvent-induced luminescence quenching: static and time-resolved X-ray absorption spectroscopy of a copper(I) phenanthroline complex.

We present a static and picosecond X-ray absorption study at the Cu K-edge of bis(2,9-dimethyl-1,10-phenanthroline)copper(I) ([Cu(dmp)2](+); dmp = 2,9-dimethyl-1,10-phenanthroline) dissolved in acetonitrile and dichloromethane. The steady-state photoluminescence spectra in dichloromethane and acetonitrile are also presented and show a shift to longer wavelengths for the latter, which points to a stronger stabilization of the excited complex. The fine structure features of the static and transient X-ray spectra allow an unambiguous assignment of the electronic and geometric structure of the molecule in both its ground and excited (3)MLCT states. Importantly, the transient spectra are remarkably similar for both solvents, and the spectral changes can be rationalized using the optimized ground- and excited-state structures of the complex. The proposed assignment of the lifetime shortening of the excited state in donor solvents (acetonitrile) to a metal-centered exciplex is not corroborated here. Molecular dynamics simulations confirm the lack of complexation; however, in both solvents the molecules come close to the metal but undergo rapid exchange with the bulk. The shortening of the lifetime of the title complex and nine additional related complexes can be rationalized by the decrease in the (3)MLCT energy. Deviations from this trend may be explained by means of the effects of the dihedral angle between the ligand planes, the solvent, and the (3)MLCT-(1)MLCT energy gap.

A wavelet analysis for the X-ray absorption spectra of molecules.

We present a Wavelet transform analysis for the X-ray absorption spectra of molecules. In contrast to the traditionally used Fourier transform approach, this analysis yields a 2D correlation plot in both R- and k-space. As a consequence, it is possible to distinguish between different scattering pathways at the same distance from the absorbing atom and between the contributions of single and multiple scattering events, making an unambiguous assignment of the fine structure oscillations for complex systems possible. We apply this to two previously studied transition metal complexes, namely iron hexacyanide in both its ferric and ferrous form, and a rhenium diimine complex, [ReX(CO)(3)(bpy)], where X = Br, Cl, or ethyl pyridine (Etpy). Our results demonstrate the potential advantages of using this approach and they highlight the importance of multiple scattering, and specifically the focusing phenomenon to the extended X-ray absorption fine structure (EXAFS) spectra of these complexes. We also shed light on the low sensitivity of the EXAFS spectrum to the Re-X scattering pathway.

Structural and magnetic dynamics of a laser induced phase transition in FeRh.

We use time-resolved x-ray diffraction and magneto-optical Kerr effect to study the laser-induced antiferromagnetic to ferromagnetic phase transition in FeRh. The structural response is given by the nucleation of independent ferromagnetic domains (τ(1)~30 ps). This is significantly faster than the magnetic response (τ(2)~60 ps) given by the subsequent domain realignment. X-ray diffraction shows that the two phases coexist on short time scales and that the phase transition is limited by the speed of sound. A nucleation model describing both the structural and magnetic dynamics is presented.

Nonthermal melting of a charge density wave in TiSe2.

We use time-resolved optical reflectivity and x-ray diffraction with femtosecond resolution to study the dynamics of the structural order parameter of the charge density wave phase in TiSe2. We find that the energy density required to melt the charge density wave nonthermally is substantially lower than that required for thermal suppression and is comparable to the charge density wave condensation energy. This observation, together with the fact that the structural dynamics take place on an extremely fast time scale, supports the exciton condensation mechanism for the charge density wave in TiSe2.

Full reconstruction of a crystal unit cell structure during coherent femtosecond motion.

We present a complete characterization of the unit cell dynamics of a laser-excited tellurium crystal using femtosecond x-ray diffraction. The analysis offers a quantitative measure of the unit cell dynamics without making any assumptions on the symmetry of the excited-state motion. The results show a large-amplitude coherently excited A(1) mode quantitatively consistent with the predictions of a density functional theory model.

Ultrafast structural phase transition driven by photoinduced melting of charge and orbital order.

We use femtosecond x-ray diffraction to probe directly the structural dynamics of a charge ordered and orbitally ordered thin film of La0.42Ca0.58MnO3 initiated by an ultrafast optical pulse. At low excitation fluences we observe the displacive excitation of a coherent optical A(g) phonon. Under high excitation conditions we observe a complete phase transition within 1 ps via the disappearance of a superlattice reflection. The initial step of the phase transition occurs on a time scale significantly faster than the 200 fs time resolution of our experiment.

Non-steroidal anti-inflammatory drugs in sports medicine: guidelines for practical but sensible use.

INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAID) are commonly used in sports medicine. NSAID have known anti-inflammatory, analgesic, antipyretic and antithrombotic effects, although their in-vivo effects in treating musculoskeletal injuries in humans remain largely unknown. NSAID analgesic action is not significantly greater than paracetamol for musculoskeletal injury but they have a higher risk profile, with side-effects including asthma exacerbation, gastrointestinal and renal side-effects, hypertension and other cardiovascular diseases. DISCUSSION: The authors recommend an approach to NSAID use in sports medicine whereby simple analgesia is preferentially used when analgesia is the primary desired outcome. However, based both on the current pathophysiological understanding of most injury presentations and the frequency that inflammation may actually be a component of the injury complex, it is premature to suppose that NSAID are not useful to the physician managing sports injuries. The prescribing of NSAID should be cautious and both situation and pathology specific. Both dose and duration minimisation should be prioritized and combined with simple principles of protection, rest, ice, compression, elevation (PRICE), which should allow NSAID-sparing. NSAID use should always be coupled with appropriate physical rehabilitation. CONCLUSION: NSAID are probably most useful for treating nerve and soft-tissue impingements, inflammatory arthropathies and tenosynovitis. They are not generally indicated for isolated chronic tendinopathy, or for fractures. The use of NSAID in treating muscle injury is controversial. Conditions in which NSAID use requires more careful assessment include ligament injury, joint injury, osteoarthritis, haematoma and postoperatively.

Establishment of detection antibodies BRRs batch 5 for in vitro potency assay of hepatitis A vaccines by ELISA.

The European Pharmacopoeia (Ph. Eur.) standard ELISA method for determination of antigen content of hepatitis A vaccines (HAV) requires specific coating and detection Biological Reference Reagents (BRRs). The 4th batch of detection antibodies BRRs was established in 2017 for use in conjunction with the Ph. Eur. General Chapter 2.7.14 Assay of hepatitis A vaccine. Stocks of these BRRs were running low and therefore the European Directorate for the Quality of Medicines and HealthCare (EDQM) organised a collaborative study to qualify replacement batches. The candidate BRR antibodies batch 5 were prepared under appropriate conditions from starting materials similar to previous batches to ensure continuity. Prior to the study, a low level of detection was obtained with new batches of the HRPO-GAM provided by the established supplier, supposedly due to a manufacturing issue in the conjugation step. Several other batches procured from the same supplier were tested without any success. Consequently HRPO-GAM batches from 3 other suppliers were tested and one batch was chosen to be included as a BRR based on its suitable characteristics. During the collaborative study, the new batches of antibodies were compared to previous batches of BRRs. Results confirmed that they were suitable to be used for the intended purpose, and could be used at the same final concentrations as the previous batch, i.e. 1:500 for the primary antibody and 1:400 for the conjugated secondary antibody. A higher background OD than in previous batches was observed, so it is recommended to subtract the background from the OD values obtained in the test in order to plot the sigmoid curve and calculate the titre of test samples. Moreover it is recommended that the first dilutions used for the IS and BRP2 should be 1:2 and 1:20, respectively, in order to achieve the same ODmax as for the previous BRRs batches. The BRRs were adopted by correspondence in October 2018 by the Ph. Eur. Commission and are presented as a set containing Hepatitis A virus primary detection antibody BRR batch 5 and Conjugated secondary detection antibody BRR batch 5. They are available from the EDQM as Hepatitis A vaccine ELISA detection antibodies set BRR batch 5.

Inception of electronic damage of matter by photon-driven post-ionization mechanisms.

"Probe-before-destroy" methodology permitted diffraction and imaging measurements of intact specimens using ultrabright but highly destructive X-ray free-electron laser (XFEL) pulses. The methodology takes advantage of XFEL pulses ultrashort duration to outrun the destructive nature of the X-rays. Atomic movement, generally on the order of >50 fs, regulates the maximum pulse duration for intact specimen measurements. In this contribution, we report the electronic structure damage of a molecule with ultrashort X-ray pulses under preservation of the atoms' positions. A detailed investigation of the X-ray induced processes revealed that X-ray absorption events in the solvent produce a significant number of solvated electrons within attosecond and femtosecond timescales that are capable of coulombic interactions with the probed molecules. The presented findings show a strong influence on the experimental spectra coming from ionization of the probed atoms' surroundings leading to electronic structure modification much faster than direct absorption of photons. This work calls for consideration of this phenomenon in cases focused on samples embedded in, e.g., solutions or in matrices, which in fact concerns most of the experimental studies.

Femtosecond phase-transition in hard x-ray excited bismuth.

The evolution of bismuth crystal structure upon excitation of its A1g phonon has been intensely studied with short pulse optical lasers. Here we present the first-time observation of a hard x-ray induced ultrafast phase transition in a bismuth single crystal at high intensities (~1014 W/cm2). The lattice evolution was followed using a recently demonstrated x-ray single-shot probing setup. The time evolution of the (111) Bragg peak intensity showed strong dependence on the excitation fluence. After exposure to a sufficiently intense x-ray pulse, the peak intensity dropped to zero within 300 fs, i.e. faster than one oscillation period of the A1g mode at room temperature. Our analysis indicates a nonthermal origin of a lattice disordering process, and excludes interpretations based on electron-ion equilibration process, or on thermodynamic heating process leading to plasma formation.

Travelling to China for the Beijing 2008 Olympic Games.

The Beijing Olympics will be the world's premier sporting event in 2008. Countries should begin planning for appropriate support for their Olympic athletes. Experienced medical staff should be appointed early and become familiar with the major medical or injury concerns of athletes and officials. Teams should assemble a comprehensive medical kit. Appropriate medical advice can ensure that athletes will arrive in Beijing in optimal condition. Medical issues particularly relevant to competitors at the Beijing Olympics include heat and humidity, waterborne diseases and air pollution. However, the air pollution probably represents less of a threat than previous media reports would indicate. The Olympic village and venues can be thought of as small enclaves located within a rapidly developing country.

Replacement, Reduction, Refinement - Animal welfare progress in European Pharmacopoeia monographs: activities of the European Pharmacopoeia Commission from 2007 to 2017.

Since the opening for signature of the European Convention for the Protection of Animals Used for Experimental and Other Scientific Purposes in 1986, the European Pharmacopoeia Commission and its experts have carried out a programme of work committed to Replacing, Reducing and Refining (3Rs) the use of animals for test purposes. While updates on achievements in the field of the 3Rs are regularly provided, this article summarises the activities of the Ph. Eur. Commission in this field within the last decade.

Internal medicine fellowship directors' perspectives on the quality and utility of letters conforming to residency program director letter of recommendation guidelines.

Background: In May 2017, the Alliance for Academic Internal Medicine (AAIM) published guidelines intending to standardize and improve internal medicine residency program director (PD) letters of recommendation (LORs) for fellowship applicants. Objectives: This study aimed to examine fellowship PDs impressions of the new guidelines, letter writers' adherence to the guidelines, and the impact of LORs that conformed to guidelines compared to non-standardized letters. Methods: The authors anonymously surveyed fellowship PDs from January to March 2018 to gather input about LORs submitted to their programs during the 2017 fellowship application cycle. Results: A total of 78% of survey respondents were satisfied with letters that followed the AAIM guidelines, whereas 48% of respondents were satisfied with letters that did not. Fellowship PDs felt that letters that followed the AAIM guidelines were more helpful than letters that did not, especially for differentiating between applicants from the same institution and for understanding residents' performance across the six core competency domains. Fellowship PDs provided several suggestions for residency PDs to make the LORs even more helpful. Conclusion: Fellowship PD respondents indicated that LORs that followed the new AAIM guidelines were more helpful than letters that did not.