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The emergence of high repetition-rate X-ray free-electron lasers (XFELs) powered by superconducting accelerator technology enables the measurement of significantly more experimental data per day than was previously possible. The European XFEL is expected to provide 27,000 pulses per second, over two orders of magnitude more than any other XFEL. The increased pulse rate is a key enabling factor for single-particle X-ray diffractive imaging, which relies on averaging the weak diffraction signal from single biological particles. Taking full advantage of this new capability requires that all experimental steps, from sample preparation and delivery to the acquisition of diffraction patterns, are compatible with the increased pulse repetition rate. Here, we show that single-particle imaging can be performed using X-ray pulses at megahertz repetition rates. The results obtained pave the way towards exploiting high repetition-rate X-ray free-electron lasers for single-particle imaging at their full repetition rate.

Background: Proton pump inhibitors (PPIs) are among the most prescribed drugs. A clinical decision support system (CDSS) could improve their rational use., Aim: The impact of an electronic algorithm (e-algorithm) implemented in a CDSS on potentially missing or inappropriately prescribed PPIs at hospital discharge, its specificity and sensitivity, and the outcome of the alerts issued were analysed., Method: An e-algorithm continuously monitored patients of a tertiary care hospital for missing or inappropriate PPIs. Following relevance assessment by a pharmacist, the alerts raised were either displayed in the patients' electronic record or dismissed. After a three-month period, all adult patients' records were retrospectively reviewed for missing or inappropriate PPIs at discharge. The results were compared with a corresponding period before CDSS introduction. Sensitivity, specificity and outcome of alerts were quantified., Results: In a 3-month period with 5018 patients, the CDSS created 158 alerts for missing PPIs and 464 alerts for inappropriate PPIs. PPI prescribing was proposed 81 times and PPI termination 122 times, with acceptance rates of 73% and 34%, respectively. A specificity of 99.4% and sensitivity of 92.0% for missing PPIs and a specificity of 97.1% and a sensitivity of 69.7% for inappropriate PPIs were calculated. The algorithm reduced incidents of missing PPIs by 63.4% (p < 0.001) and of inappropriate PPIs by 16.2% (p = 0.022)., Conclusion: The algorithm identified patients without necessary gastroprotection or inappropriate PPIs with high specificity and acceptable sensitivity. It positively impacted the rational use of PPIs by reducing incidents of missing and inappropriate PPIs., (© 2024. The Author(s).)

Background: As the most commonly used illicit substance, cannabis is gaining global acceptance through increasing legalization efforts. This shift intensifies the need for research to guide policymakers and healthcare providers in harm reduction and treatment strategies. Nonetheless, the relationship between psychopathological symptoms and cannabis use remains inadequately understood., Methods: A sample of regular cannabis consumers completed self-reported assessments for depression (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), Attention-Deficit/Hyperactivity Disorder (ADHD; Adult ADHD Self-Report Scale V1.1), and psychosis (Early Recognition Inventory based on IRAOS) as well as previous black-market cannabis use patterns. Cannabis Use Disorder Identification Test Revised (CUDIT-R) was used to identify cannabis use disorder (CUD). To understand psychopathological symptom load related to cannabis consumption as well as cannabis use motives, multiple regression models were performed to identify psychopathological variables predicting cannabis use frequency and quantity. Linear regression and correlation analyses were conducted, adjusting for relevant covariates (age, gender, education, alcohol, other substance use)., Results: Three-hundred-sixty regular cannabis users interested in a study on regulated cannabis access in Basel, Switzerland were examined. In bivariate analysis, cannabis use frequency correlated with depressive ( r (358) = 0.16, p  = 0.003) and anxiety symptom load ( r (358) = 0.11, p  = 0.034). Cannabis quantity correlated with depressive ( r (358) = 0.15, p  = 0.005), ADHD ( r (358) = 0.14, p  = 0.008), and psychosis symptom load ( r (358) = 0.16, p  = 0.002). However, in the adjusted regression models only depressive and ADHD symptom loads were significantly associated with cannabis use frequency ( p  = 0.006 and p  = 0.034, respectively) and quantity ( p  = 0.037 and p  = 0.019, respectively). No significant correlations between cannabis consumption and anxiety or psychosis remained after adjustment., Conclusion: ADHD and depressive symptoms correlate with increased cannabis use in a cohort of regular users, suggesting potential self-medication in nonclinical populations. With the rising availability of cannabis worldwide, these results highlight the necessity for longitudinal studies to disentangle the complex dynamics between cannabis consumption and mental health symptoms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mosandl, Baltes-Flückiger, Kronschnabel, Meyer, Guessoum, Herrmann, Vogel, Walter and Pichler.)

Introduction: There is considerable effort in legalizing recreational use of cannabis globally. The successful implementation of a program of regulated access to recreational cannabis (PRAC) depends on the consumers' engagement. The aim of this study was to examine the acceptability of twelve different regulatory aspects by cannabis users including those obtaining cannabis from the illicit market and vulnerable populations such as young adults and problematic users., Methods: The current study is a multisite online survey conducted in Switzerland. A total of 3,132 adult Swiss residents who consumed cannabis within the previous 30 days represented the studied population. Mean age was 30.5 years, 80.5% were men, and 64.2% of the participants stated that they always or often obtain cannabis from the illicit market. We described consumers' acceptability of twelve regulatory aspects concerning THC content control, disclosure of sensitive personal data, security aspects, and follow-up procedures by applying descriptive statistics and multiple regression models., Results: THC content regulation showed most discrepancy with 89.4% of the participants stating to engage in a PRAC if five different THC contents were available as compared to 54% if only 12% THC was available. The least accepted regulatory aspect was disposal of contact details with an acceptability rate of 18.1%. Consumers mainly obtaining cannabis from the illicit market, young adults, and problematic users showed similar acceptability patterns. Participants obtaining cannabis from the illicit market were more likely to engage in a PRAC if five different THC contents were available as compared to participants obtaining cannabis from other sources (OR 1.94, 95% CI: 1.53-2.46)., Conclusion: A carefully designed PRAC that takes into account the consumers' perspective is likely to transfer them to the regulated market and to engage vulnerable populations. We cannot recommend the distribution of cannabis with only 12% THC content as this is unlikely to engage the target population., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The FMS-like tyrosine kinase 3 ( FLT3 ) gene is mutated in one-third of patients with de novo acute myeloid leukemia (AML). Mutated FLT3 variants are constitutively active kinases signaling via AKT kinase, MAP kinases, and STAT5. FLT3 inhibitors have been approved for the treatment of FLT3 -mutated AML. However, treatment response to FLT3 inhibitors may be short-lived, and resistance may emerge. Compounds targeting STAT5 may enhance and prolong effects of FLT3 inhibitors in this subset of patients with FLT3 -mutated AML. Here STAT5-inhibitor AC-4-130, FLT3 inhibitor midostaurin (PKC412), BMI-1 inhibitor PTC596, MEK-inhibitor trametinib, MCL1-inhibitor S63845, and BCL-2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. Synergistic effects on cell viability were detected in both FLT3 -mutated and FLT3 -wild-type AML cells treated with AC-4-130 in combination with the MCL1 inhibitor S63845. AML patient samples with a strong response to AC-4-130 and S63845 combination treatment were characterized by mutated FLT3 or mutated TET2 genes. Susceptibility of AML cells to AC-4-130, PTC596, trametinib, PKC412, and venetoclax was altered in the presence of HS-5 stroma. Only the MCL1 inhibitor S63845 induced cell death with equal efficacy in the absence or presence of bone marrow stroma. The combination of the STAT5-inhibitor AC-4-130 and the MCL1 inhibitor S63845 may be an effective treatment targeting FLT3 -mutated or TET2 -mutated AML.

We have recorded the diffraction patterns from individual xenon clusters irradiated with intense extreme ultraviolet pulses to investigate the influence of light-induced electronic changes on the scattering response. The clusters were irradiated with short wavelength pulses in the wavelength regime of different 4d inner-shell resonances of neutral and ionic xenon, resulting in distinctly different optical properties from areas in the clusters with lower or higher charge states. The data show the emergence of a transient structure with a spatial extension of tens of nanometers within the otherwise homogeneous sample. Simulations indicate that ionization and nanoplasma formation result in a light-induced outer shell in the cluster with a strongly altered refractive index. The presented resonant scattering approach enables imaging of ultrafast electron dynamics on their natural timescale., (© 2020 Author(s).)

Intense x-ray free-electron laser (XFEL) pulses hold great promise for imaging function in nanoscale and biological systems with atomic resolution. So far, however, the spatial resolution obtained from single shot experiments lags averaging static experiments. Here we report on a combined computational and experimental study about ultrafast diffractive imaging of sucrose clusters which are benchmark organic samples. Our theoretical model matches the experimental data from the water window to the keV x-ray regime. The large-scale dynamic scattering calculations reveal that transient phenomena driven by non-linear x-ray interaction are decisive for ultrafast imaging applications. Our study illuminates the complex interplay of the imaging process with the rapidly changing transient electronic structures in XFEL experiments and shows how computational models allow optimization of the parameters for ultrafast imaging experiments.

People who believe that willpower is not limited exhibit higher self-regulation and well-being than people who believe that willpower is a limited resource. So far, only little is known about the antecedents of people's beliefs about willpower. Three studies examine whether autonomous goal striving promotes the endorsement of a nonlimited belief and whether this relationship is mediated by vitality, the feeling of being awake and energetic. Study 1 ( n = 208) showed that autonomous goal striving predicts a change in willpower beliefs over 4 months and that this change is mediated by vitality. Study 2 ( n = 92) replicated this finding using experience sampling assessments of vitality. Experimental Study 3 ( n = 243) showed that inducing an autonomous mind-set enhances people's endorsement of a nonlimited belief by fostering vitality. The studies support the idea that what people believe about willpower depends, at least in part, on recent experiences with tasks as being energizing or draining.

Extreme ultraviolet (XUV) and X-ray free-electron lasers enable new scientific opportunities. Their ultra-intense coherent femtosecond pulses give unprecedented access to the structure of undepositable nanoscale objects and to transient states of highly excited matter. In order to probe the ultrafast complex light-induced dynamics on the relevant time scales, the multi-purpose end-station CAMP at the free-electron laser FLASH has been complemented by the novel multilayer-mirror-based split-and-delay unit DESC (DElay Stage for CAMP) for time-resolved experiments. XUV double-pulses with delays adjustable from zero femtoseconds up to 650 picoseconds are generated by reflecting under near-normal incidence, exceeding the time range accessible with existing XUV split-and-delay units. Procedures to establish temporal and spatial overlap of the two pulses in CAMP are presented, with emphasis on the optimization of the spatial overlap at long time-delays via time-dependent features, for example in ion spectra of atomic clusters., (open access.)

Objectives: The use of platelet concentrates has gained increasing awareness in recent years for regenerative procedures in modern dentistry. The aim of the present study was to compare growth factor release over time from platelet-rich plasma (PRP), platelet-rich fibrin (PRF), and a modernized protocol for PRF, advanced-PRF (A-PRF)., Materials and Methods: Eighteen blood samples were collected from six donors (3 samples each for PRP, PRF, and A-PRF). Following preparation, samples were incubated in a plate shaker and assessed for growth factor release at 15 min, 60 min, 8 h, 1 day, 3 days, and 10 days. Thereafter, growth factor release of PDGF-AA, PDGF-AB, PDGF-BB, TGFB1, VEGF, EGF, and IGF was quantified using ELISA., Results: The highest reported growth factor released from platelet concentrates was PDGF-AA followed by PDGF-BB, TGFB1, VEGF, and PDGF-AB. In general, following 15-60 min incubation, PRP released significantly higher growth factors when compared to PRF and A-PRF. At later time points up to 10 days, it was routinely found that A-PRF released the highest total growth factors. Furthermore, A-PRF released significantly higher total protein accumulated over a 10-day period when compared to PRP or PRF., Conclusion: The results from the present study indicate that the various platelet concentrates have quite different release kinetics. The advantage of PRP is the release of significantly higher proteins at earlier time points whereas PRF displayed a continual and steady release of growth factors over a 10-day period. Furthermore, in general, it was observed that the new formulation of PRF (A-PRF) released significantly higher total quantities of growth factors when compared to traditional PRF., Clinical Relevance: Based on these findings, PRP can be recommended for fast delivery of growth factors whereas A-PRF is better-suited for long-term release.

We studied the nanoplasma formation and explosion dynamics of single large xenon clusters in ultrashort, intense x-ray free-electron laser pulses via ion spectroscopy. The simultaneous measurement of single-shot diffraction images enabled a single-cluster analysis that is free from any averaging over the cluster size and laser intensity distributions. The measured charge state-resolved ion energy spectra show narrow distributions with peak positions that scale linearly with final ion charge state. These two distinct signatures are attributed to highly efficient recombination that eventually leads to the dominant formation of neutral atoms in the cluster. The measured mean ion energies exceed the value expected without recombination by more than an order of magnitude, indicating that the energy release resulting from electron-ion recombination constitutes a previously unnoticed nanoplasma heating process. This conclusion is supported by results from semiclassical molecular dynamics simulations.

The diversity of nanoparticle shapes generated by condensation from gaseous matter reflects the fundamental competition between thermodynamic equilibration and the persistence of metastable configurations during growth. In the kinetically limited regime, intermediate geometries that are favoured only in early formation stages can be imprinted in the finally observed ensemble of differently structured specimens. Here we demonstrate that single-shot wide-angle scattering of femtosecond soft X-ray free-electron laser pulses allows three-dimensional characterization of the resulting metastable nanoparticle structures. For individual free silver particles, which can be considered frozen in space for the duration of photon exposure, both shape and orientation are uncovered from measured scattering images. We identify regular shapes, including species with fivefold symmetry and surprisingly large aspect ratio up to particle radii of the order of 100 nm. Our approach includes scattering effects beyond Born's approximation and is remarkably efficient-opening up new routes in ultrafast nanophysics and free-electron laser science.

Extremely large xenon clusters with sizes exceeding the predictions of the Hagena scaling law by several orders of magnitude are shown to be produced in pulsed gas jets. The cluster sizes are determined using single-shot single-particle imaging experiments with short-wavelength light pulses from the free-electron laser in Hamburg (FLASH). Scanning the time delay between the pulsed cluster source and the intense femtosecond x-ray pulses first shows a main plateau with size distributions in line with the scaling laws, which is followed by an after-pulse of giant clusters. For the extremely large clusters with radii of several hundred nanometers the x-ray scattering patterns indicate a grainy substructure of the particles, suggesting that they grow by cluster coagulation.

Stable isotope ratios of H, C, and O are powerful indicators of a wide variety of planetary geophysical processes, and for Mars they reveal the record of loss of its atmosphere and subsequent interactions with its surface such as carbonate formation. We report in situ measurements of the isotopic ratios of D/H and (18)O/(16)O in water and (13)C/(12)C, (18)O/(16)O, (17)O/(16)O, and (13)C(18)O/(12)C(16)O in carbon dioxide, made in the martian atmosphere at Gale Crater from the Curiosity rover using the Sample Analysis at Mars (SAM)'s tunable laser spectrometer (TLS). Comparison between our measurements in the modern atmosphere and those of martian meteorites such as ALH 84001 implies that the martian reservoirs of CO2 and H2O were largely established ~4 billion years ago, but that atmospheric loss or surface interaction may be still ongoing.

Objectives: The purpose of the present study was to compare the efficacy of chemomechanical caries removal (Carisolv) to conventional hand excavation in deciduous teeth., Methods: Twenty-two freshly extracted teeth with varying degree of caries were treated using both of these methods. One part of each caries lesion was prepared using the Carisolv method and the other part using conventional hand excavation. The third (middle) part was left untreated to serve as control. Histological preparations of each tooth were then made and examined in order to compare the quality of the preparations. Length and area of residual caries, microhardness of the dentine in each group and time needed for preparation were analysed., Results: The results showed that there was no significant difference in the amount of residual caries in the cavity walls treated using the two methods., Conclusions: The Carisolv method was significantly more time consuming than conventional preparation using hand excavator. However, both methods removed caries efficiently.

The aim of this study was to evaluate the effect of deproteinized bovine bone graft material on new bone formation in a guided bone regeneration model system. In 20 rabbits, a periosteal skin flap was raised uncovering the calvaria. A form stable hemispherical dome made of poly-lactic acid (PLA) was placed onto the roughened calvaria. Prior to placement, the dome was either filled with peripheral blood alone (control group, 8 rabbits), or with blood and OsteoGraf/N-300 (test group, 12 rabbits). The wound was closed for primary healing. Morphometric assessment of 1- and 2-month undecalcified histologic specimens revealed better tissue fill in the test domes at 1 month (test 99%, control 55%) (P < 0.05) and 2 months (t, 100%; c, 82%). The fraction of the new bone within the regenerated tissue was higher in the test specimens at 1 month (t, 22%; c, 12%) (P < 0.05) and 2 months (t, 34%; c, 24%). The fraction of the entire space underneath the domes occupied by bone was higher in the test at 1 month, but higher in the controls at 2 months. The fraction of the bone substitute material in contact with bone increased from 1 month (34% +/- 14) to 2 months (45% +/- 5). The surface fraction of osteoblast layers was tendentially higher in the test at 1 month but higher in the control specimens at 2 months. In both test and control, initially woven bone was formed which underwent subsequent remodeling. Cellular degradation of the deproteinized bone graft was frequently detected. It is concluded that deproteinized bovine bone mineral has osteoconductive properties and can initially accelerate new bone formation during guided bone regeneration by increased recruitment of osteoblasts.