Antibodies and complement are key drivers of thrombosis.

Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcµR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic vicious circle. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis.

Challenges for the management of Johne's disease in the UK: Expectation management, space, 'free riding', and vet-farmer communication.

Johne's disease in cattle is a significant global animal health challenge. Johne's disease is chronic, affecting the gastrointestinal tract of cattle and other ruminants and is caused by the bacteria Mycobacterium avium ssp. Paratuberculosis. Many countries have introduced schemes and programmes to try and control the spread of Johne's disease, including the UK. Despite efforts to control it, however, Johne's disease remains consistently ranked by UK producers as the top ranked disease negatively affecting productivity, indicating that schemes are not perceived to have solved the problem fully. Building on a global systematic review of the literature on barriers and solutions for Johne's disease control on-farm, we conducted an empirical study with over 400 farmers and 150 veterinary professionals across the UK. The study used workshops and semi-structured interviews to understand better the challenges dairy farmers and veterinarians face in implementing on-farm Johne's disease management schemes with the aim of identifying solutions. The study found that four main challenges are faced in the on-farm control of Johne's - (1) Management of farmer expectations around Johne's disease, with eradication near impossible, (2) Issues regarding space for segregation and the related economics of control (3) A 'free-riding' problem which can be influenced by the voluntary nature of control plans and (4) Challenges in vet-farmer communication, including levels of knowledge. Our findings have relevance for the control of Johne's disease in the UK and other countries, including for regions with voluntary and compulsory control programmes.

Exploring inclusion in UK agricultural robotics development: who, how, and why?

The global agricultural sector faces a significant number of challenges for a sustainable future, and one of the tools proposed to address these challenges is the use of automation in agriculture. In particular, robotic systems for agricultural tasks are being designed, tested, and increasingly commercialised in many countries. Much touted as an environmentally beneficial technology with the ability to improve data management and reduce the use of chemical inputs while improving yields and addressing labour shortages, agricultural robotics also presents a number of potential ethical challenges - including rural unemployment, the amplification of economic and digital inequalities, and entrenching unsustainable farming practices. As such, development is not uncontroversial, and there have been calls for a responsible approach to their innovation that integrates more substantive inclusion into development processes. This study investigates current approaches to participation and inclusion amongst United Kingdom (UK) agricultural robotics developers. Through semi-structured interviews with key members of the UK agricultural robotics sector, we analyse the stakeholder engagement currently integrated into development processes. We explore who is included, how inclusion is done, and what the inclusion is done for. We reflect on how these findings align with the current literature on stakeholder inclusion in agricultural technology development, and suggest what they could mean for the development of more substantive responsible innovation in agricultural robotics.

Dual-beam X-ray nano-holotomography.

Nanotomography with hard X-rays is a widely used technique for high-resolution imaging, providing insights into the structure and composition of various materials. In recent years, tomographic approaches based on simultaneous illuminations of the same sample region from different angles by multiple beams have been developed at micrometre image resolution. Transferring these techniques to the nanoscale is challenging due to the loss in photon flux by focusing the X-ray beam. We present an approach for multi-beam nanotomography using a dual-beam Fresnel zone plate (dFZP) in a near-field holography setup. The dFZP generates two nano-focused beams that overlap in the sample plane, enabling the simultaneous acquisition of two projections from slightly different angles. This first proof-of-principle implementation of the dual-beam setup allows for the efficient removal of ring artifacts and noise using machine-learning approaches. The results open new possibilities for full-field multi-beam nanotomography and pave the way for future advancements in fast holotomography and artifact-reduction techniques.

Optimization of contrast and dose in x-ray phase-contrast tomography with a Talbot-Lau interferometer.

X-ray phase-contrast imaging has become a valuable tool for biomedical research due to its improved contrast abilities over regular attenuation-based imaging. The recently emerged Talbot-Lau interferometer can provide quantitative attenuation, phase-contrast and dark-field image data, even with low-brilliance x-ray tube sources. Thus, it has become a valid option for clinical environments. In this study, we analyze the effects of x-ray tube voltage and total number of images on the contrast-to-noise ratio (CNR) and dose-weighted CNR (CNRD) calculated from tomographic transmission and phase-contrast data of a phantom sample. Constant counting statistics regardless of the voltage was ensured by adjusting the image exposure time for each voltage setting. The results indicate that the x-ray tube voltage has a clear effect on both image contrast and noise. This effect is amplified in the case of phase-contrast images, which is explained by the polychromatic x-ray spectrum and the dependence of interferometer visibility on the spectrum. CNRD is additionally affected by the total imaging time. While submerging the sample into a water container effectively reduces image artefacts and improves the CNR, the additional attenuation of the water must be compensated with a longer exposure time. This reduces dose efficiency. Both the CNR and CNRD are higher in the phase-contrast images compared to transmission images. For transmission images, and phase-contrast images without the water container, CNRD can be increased by using higher tube voltages (in combination with a lower exposure time). For phase-contrast images with the water container, CNRD is increased with lower tube voltages. In general, the CNRD does not strongly depend on the number of tomographic angles or phase steps used.

Transient X-Ray Absorption Near Edge Structure Spectroscopy Using Broadband Free-Electron Laser Pulses.

A new method for time-resolved X-ray absorption near edge structure (XANES) spectroscopy that enables faster data acquisition and requires smaller sample quantities for high-quality data, thus allowing the analysis of more samples in a shorter time is introduced. The method uses large bandwidth free electron laser pulses to measure laser-excited XANES spectra in transmission mode. A beam-splitting grating configuration allows simultaneous measurements of the spectra of the incoming X-ray Free Electron Laser (XFEL) pulses and transmission XANES, which is crucial for compensating the pulse-dependent intensity and spectrum fluctuations due to the self-amplified spontaneous emission operation. The implementation of this new methodology is applied on a liquid solution of ammonium iron(III) oxalate jet and is compared to previous results, showing great improvements in the speed of acquisition and spectral resolution, and the ability to measure a large 2-D spectral-time map quickly.

Interplay of Andreev Reflection and Coulomb Blockade in Hybrid Superconducting Single-Electron Transistors.

We study the interplay between Coulomb blockade and superconductivity in a tunable superconductor-superconductor-normal-metal single-electron transistor. The device is realized by connecting the superconducting island via an oxide barrier to the normal-metal lead and with a break junction to the superconducting lead. The latter enables Cooper pair transport and (multiple) Andreev reflection. We show that these processes are relevant also far above the superconducting gap and that signatures of Coulomb blockade may reoccur at high bias while they are absent for small bias in the strong-coupling regime. Our experimental findings agree with simulations using a rate equation approach in combination with the full counting statistics of multiple Andreev reflection.

Compact single-shot soft X-ray photon spectrometer for free-electron laser diagnostics.

The photon spectrum from free-electron laser (FEL) light sources offers valuable information in time-resolved experiments and machine optimization in the spectral and temporal domains. We have developed a compact single-shot photon spectrometer to diagnose soft X-ray spectra. The spectrometer consists of an array of off-axis Fresnel zone plates (FZP) that act as transmission-imaging gratings, a Ce:YAG scintillator, and a microscope objective to image the scintillation target onto a two-dimensional imaging detector. This spectrometer operates in segmented energy ranges which covers tens of electronvolts for each absorption edge associated with several atomic constituents: carbon, nitrogen, oxygen, and neon. The spectrometer's performance is demonstrated at a repetition rate of 120 Hz, but our detection scheme can be easily extended to 200 kHz spectral collection by employing a fast complementary metal oxide semiconductor (CMOS) line-scan camera to detect the light from the scintillator. This compact photon spectrometer provides an opportunity for monitoring the spectrum downstream of an endstation in a limited space environment with sub-electronvolt energy resolution.

Electron population dynamics in resonant non-linear x-ray absorption in nickel at a free-electron laser.

Free-electron lasers provide bright, ultrashort, and monochromatic x-ray pulses, enabling novel spectroscopic measurements not only with femtosecond temporal resolution: The high fluence of their x-ray pulses can also easily enter the regime of the non-linear x-ray-matter interaction. Entering this regime necessitates a rigorous analysis and reliable prediction of the relevant non-linear processes for future experiment designs. Here, we show non-linear changes in the L3-edge absorption of metallic nickel thin films, measured with fluences up to 60 J/cm2. We present a simple but predictive rate model that quantitatively describes spectral changes based on the evolution of electronic populations within the pulse duration. Despite its simplicity, the model reaches good agreement with experimental results over more than three orders of magnitude in fluence, while providing a straightforward understanding of the interplay of physical processes driving the non-linear changes. Our findings provide important insights for the design and evaluation of future high-fluence free-electron laser experiments and contribute to the understanding of non-linear electron dynamics in x-ray absorption processes in solids at the femtosecond timescale.

Factors that influence dairy farmers' decisions to implement Johne's Disease control practices: A systematic review.

Johne's Disease (JD) is an infectious ruminant disease that can cause economic loss for famers through reduced milk yields and infertility and has negative implications for animal welfare. JD is endemic in the dairy populations of many countries and there has been significant effort by governments and industry to try and control it. However, these efforts have had limited success. Many studies look at individual control programmes or the adoption of Johne's control measures; however a wider perspective on what drives farmer participation Johne's control does not currently exist. This study seeks to fill this gap by conducting a systematic review informed by the PRISMA statement. The results suggest that psychological factors such as participation fatigue, cognitive dissidence over animal welfare and not having first-hand experience of the disease act as barriers to Johne's control. To better promote Johne's control, this review emphasises that control programmes need to engage farmers, advisers, and supply chain actors in their design and delivery of control programmes to account for differing attitudes and levels of knowledge.

Hard X-ray stereographic microscopy for single-shot differential phase imaging.

The characterisation of fast phenomena at the microscopic scale is required for the understanding of catastrophic responses of materials to loads and shocks, the processing of materials by optical or mechanical means, the processes involved in many key technologies such as additive manufacturing and microfluidics, and the mixing of fuels in combustion. Such processes are usually stochastic in nature and occur within the opaque interior volumes of materials or samples, with complex dynamics that evolve in all three dimensions at speeds exceeding many meters per second. There is therefore a need for the ability to record three-dimensional X-ray movies of irreversible processes with resolutions of micrometers and frame rates of microseconds. Here we demonstrate a method to achieve this by recording a stereo phase-contrast image pair in a single exposure. The two images are combined computationally to reconstruct a 3D model of the object. The method is extendable to more than two simultaneous views. When combined with megahertz pulse trains of X-ray free-electron lasers (XFELs) it will be possible to create movies able to resolve 3D trajectories with velocities of kilometers per second.

Litigation associated with 5-alpha-reductase-inhibitor use: A Canadian legal database review.

INTRODUCTION: 5α-reductase inhibitors (5ARI) are commonly prescribed medications. There is ongoing controversy about the adverse events of these medications. The aim of this study is to characterize lawsuits in Canada involving medical complications of 5ARIs use. MATERIALS AND METHODS: Legal cases were queried from CanLII. Cases were included if they involved a party taking a 5ARI who alleged an adverse event. Relevant full cases were retained, and pertinent characteristics were extracted with the help of a legal expert. RESULTS: Our deduplicated search yielded 67 unique legal documents from December 2013 to February 2019. Twelve of these documents met the inclusion criteria (representing 3 cases, considering each case had several hearings). The medical complaints filed by the plaintiffs were all related to medication side effects (n = 3, 100%). The plaintiffs were commonly patients themselves. Defendants were exclusively pharmaceutical companies. Persistent erectile dysfunction after stopping the medication was cited as a side effect in all complaints. The prescriptions were made for male pattern hair loss (n = 3, 100%) in all cases. All cases represent class actions brought by the plaintiffs, and they have been certified by their respective court. However, the cases are still ongoing. CONCLUSION: While 5ARI use has been linked to undesired sexual side effects, there have been few litigations on this issue in Canada. Persisting sexual dysfunction after stopping the medication is the only complaint presented in legal action. To date, no judgment against a physician or pharmaceutical company was identified. Cases are still ongoing.

Apochromatic X-ray focusing.

Achromatic doublets are combinations of two individual lenses designed to focus different wavelengths of light in the same position. Apochromatic optics are improved versions of the achromatic schemes which extend the wavelength range significantly. Both achromatic and apochromatic optics are well-established for visible light. However, X-ray achromatic lenses did not exist until very recently, and X-ray apochromatic lenses have never been experimentally demonstrated. Here, we create an X-ray apochromatic lens system using an appropriate combination of a Fresnel zone plate and a diverging compound refractive lens with a tuned separation distance. The energy-dependent performance of this apochromat was characterized at photon energies between 6.5 and 13.0 keV by ptychographic reconstruction of the focal spot and scanning transmission X-ray microscopy of a resolution test sample. The apochromat delivered a reconstructed focal spot size of 940 × 740 nm2. The apochromatic combination shows a four-fold improvement in the chromatic aberration correction range compared to an achromatic doublet configuration. Thus, apochromatic X-ray optics have the potential to increase the focal spot intensity for a wide variety of X-ray applications.

Virtually Augmented Self-Hypnosis in Peripheral Vascular Intervention: A Randomized Controlled Trial.

PURPOSE: Hypnosis is useful for diminishing distress during medical procedures. This study investigated the efficacy of virtually augmented self-hypnosis as an adjunctive non-pharmacological method for procedural pain and anxiety relief during endovascular interventions (EVI). METHODS: We compared an immersive distraction experience (clinicaltrials.gov identifier NCT04561596) featuring virtual reality (VR) using a head-mounted display versus treatment as usual (TAU). Patients followed the "Aqua" module (Oncomfort™) consisting of a scuba dive and breathing exercises. They experienced a self-induced dissociative state similar to clinical hypnosis without direct intervention of a professional. Enrollment followed a 1:1 randomized open study (VR or TAU). Patients' feelings were evaluated just before and after the procedure, and 3 months following intervention. Anxiety was evaluated using the State Trait Anxiety Inventory (STAI) and pain (sensory, emotional, and memory) with a visual analogue scale (VAS). RESULTS: This study included 100 patients. Mean anxiety (pre-post) was significantly reduced within groups and between groups (difference of 4.2 points, p = 0.016). The percentage of responders to anxiety lowering were 76 and 46% for VR and TAU, respectively (p = 0.004). The two groups did not significantly differ in mean sensory-intensity and affective emotional pain (pre-post) using VAS, in negative memories concerning remembered pain at 3 months (difference > 1 from immediate post-procedural reported pain intensity), mean procedural time, or the need for analgesic or sedative drugs. CONCLUSIONS: VR self-hypnosis has the potential to improve the management of patients' distress during radiological procedures. It is safe and effective for reducing anxiety during EVI.

Hard X-ray full-field nanoimaging using a direct photon-counting detector.

Full-field X-ray nanoimaging is a widely used tool in a broad range of scientific areas. In particular, for low-absorbing biological or medical samples, phase contrast methods have to be considered. Three well established phase contrast methods at the nanoscale are transmission X-ray microscopy with Zernike phase contrast, near-field holography and near-field ptychography. The high spatial resolution, however, often comes with the drawback of a lower signal-to-noise ratio and significantly longer scan times, compared with microimaging. In order to tackle these challenges a single-photon-counting detector has been implemented at the nanoimaging endstation of the beamline P05 at PETRA III (DESY, Hamburg) operated by Helmholtz-Zentrum Hereon. Thanks to the long sample-to-detector distance available, spatial resolutions of below 100 nm were reached in all three presented nanoimaging techniques. This work shows that a single-photon-counting detector in combination with a long sample-to-detector distance allows one to increase the time resolution for in situ nanoimaging, while keeping a high signal-to-noise level.

Refractive axicon for X-ray microscopy applications: design, optimization, and experiment.

In a full-field transmission X-ray microscopy (TXM) setup, a condenser X-ray optical element is used to illuminate the sample by condensing the X-ray beam delivered by the synchrotron storage ring. On-going and future upgrades of synchrotron facilities to diffraction-limited storage rings will pose new challenges to these TXM setups, such as much smaller X-ray beams on the condenser. Here, we demonstrate that a refractive axicon can be used as an X-ray beam shaper to match the ring-shaped aperture of the condenser. Aiming at more efficient use of the incoming X-ray intensity, we explore several axicon designs both analytically and with numerical simulations. The axicons were produced by two-photon polymerization 3D printing on thin silicon nitride membrane substrates. The first characterization of the axicon was carried out at the TOMCAT beamline of the Swiss Light Source (Switzerland).

Advancements in Liquid Jet Technology and X-ray Spectroscopy for Understanding Energy Conversion Materials during Operation.

ConspectusWater splitting is intensively studied for sustainable and effective energy storage in green/alternative energy harvesting-storage-release cycles. In this work, we present our recent developments for combining liquid jet microtechnology with different types of soft X-ray spectroscopy at high-flux X-ray sources, in particular developed for studying the oxygen evolution reaction (OER). We are particularly interested in the development of in situ photon-in/photon-out techniques, such as in situ resonant inelastic X-ray scattering (RIXS) techniques at high-repetition-frequency X-ray sources, pointing toward operando capabilities. The pilot catalytic systems we use are perovskites having the general structure ABO3 with lanthanides or group II elements at the A sites and transition metals at the B sites. Depending on the chemical substitutions of ABO3, their catalytic activity for OER can be tuned by varying the composition.In this work, we present our in situ RIXS studies of the manganese L-edge of perovskites during OER. We have developed various X-ray spectroscopy approaches like transmission zone plate-, reflection zone plate-, and grating-based emission spectroscopy techniques. Combined with tunable incident X-ray energies, we yield complementary information about changing (inverse) X-ray absorption features of the perovskites, allowing us to deduce element- and oxidation-state-specific chemical monitoring of the catalyst. Adding liquid jet technology, we monitor element- and oxidation-state-specific interactions of the catalyst with water adsorbate during OER. By comparing the different technical spectroscopy approaches combined with high-repetition-frequency experiments at synchrotrons and free-electron lasers, we conclude that the combination of liquid jet with low-resolution zone-plate-based X-ray spectroscopy is sufficient for element- and oxidation-state-specific chemical monitoring during OER and easy to handle.For an in-depth study of OER mechanisms, however, including the characterization of catalyst-water adsorbate in terms of their charge transfer properties and especially valence intermediates formed during OER, high-resolution spectroscopy tools based on a combination of liquid jets with gratings bear bigger potential since they allow resolution of otherwise-overlapping X-ray spectroscopy transitions. Common for all of these experimental approaches is the conclusion that without the versatile developments of liquid jets and liquid beam technologies, elaborate experiments such as high-repetition experiments at high-flux X-ray sources (like synchrotrons or free-electron lasers) would hardly be possible. Such experiments allow sample refreshment for every single X-ray shot for repetition frequencies of up to 5 MHz, so that it is possible (a) to study X-ray-radiation-sensitive samples and also (b) to utilize novel types of flux-hungry X-ray spectroscopy tools like photon-in/photon-out X-ray spectroscopy to study the OER.

The old, the new, or the old made new? Everyday counter-narratives of the so-called fourth agricultural revolution.

Prevalent narratives of agricultural innovation predict that we are once again on the cusp of a global agricultural revolution. According to these narratives, this so-called fourth agricultural revolution, or agriculture 4.0, is set to transform current agricultural practices around the world at a quick pace, making use of new sophisticated precision technologies. Often used as a rhetorical device, this narrative has a material effect on the trajectories of an inherently political and normative agricultural transition; with funding, other policy instruments, and research attention focusing on the design and development of new precision technologies. A growing critical social science literature interrogates the promises of revolution. Engagement with new technology is likely to be uneven, with benefits potentially favouring the already powerful and the costs falling hardest on the least powerful. If grand narratives of change remain unchallenged, we risk pursuing innovation trajectories that are exclusionary, failing to achieve responsible innovation. This study utilises a range of methodologies to explore everyday encounters between farmers and technology, with the aim of inspiring further work to compile the microhistories that can help to challenge robust grand narratives of change. We explore how farmers are engaging with technology in practice and show how these interactions problematise a simple, linear notion of innovation adoption and use. In doing so, we reflect upon the contribution that the study of everyday encounters can make in setting more inclusionary, responsible pathways towards sustainable agriculture.

The Impact of COVID-19 on Farmers' Mental Health: A Case Study of the UK.

OBJECTIVES: In this paper, we use a UK case study to explore how the COVID-19 pandemic affected the mental health (emotional, psychological, social wellbeing) of farmers. We outline the drivers of poor farming mental health, the manifold impacts of the pandemic at a time of policy and environmental change, and identify lessons that can be learned to develop resilience in farming communities against future shocks. METHODS: We undertook a survey answered by 207 farmers across the UK, focusing on drivers of poor mental health and the effect of the COVID-19 pandemic. We also conducted 22 in-depth interviews with individuals in England, Scotland and Wales who provide mental health support to farmers. These explored how and why the COVID-19 pandemic affected the mental health of farmers. These interviews were supplemented by 93 survey responses from a similar group of support providers (UK-wide). RESULTS: We found that the pandemic exacerbated underlying drivers of poor mental health and wellbeing in farming communities. 67% of farmers surveyed reported feeling more stressed, 63% felt more anxious, 38% felt more depressed, and 12% felt more suicidal. The primary drivers of poor mental health identified by farmers during the pandemic included decreased social contact and loneliness, issues with the general public on private land, and moving online for social events. Support providers also highlighted relationship and financial issues, illness, and government inspections as drivers of poor mental health. Some farmers, conversely, outlined positive impacts of the pandemic. CONCLUSION: The COVID-19 pandemic is just one of many potential stressors associated with poor farming mental health and its impacts are likely to be long-lasting and delayed. Multiple stressors affecting farmers at the same time can create a tipping point. Therefore, there is a need for long-term support and ongoing evaluation of the drivers of poor mental health in farming families.