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Molten metal catalysts for methane pyrolysis and dry reforming are becoming recognized for their potential in decarbonization efforts. Their use in bubble column reactors facilitates continuous operation by allowing the produced carbon to float to the surface for removal. While most reported molten metals produce low-value amorphous carbon or graphitic sheets containing some metals, our study introduces a Cu-In alloy that selectively produces high-purity carbon nanofibers. These nanofibers are tubular and have a smooth or bamboo-like segmented structure with a diameter of approximately 100 nm. We have identified a droplet-based pathway for the growth of these fibers and removal of the droplets, observed consistently across a bubble column reactor, a surface reactor, and both in the absence and presence of carbon dioxide for pyrolysis and dry reforming. The molten Cu-In system is shown to outperform other molten metal catalysts, producing fibers with a purity greater than 99.9% after heat treatment.

Biosensors play key roles in medical research and diagnostics. However, the development of biosensors for new biomolecular targets of interest often involves tedious optimization steps to ensure a high signal response at the analyte concentration of interest. Here we show a modular nanosensor platform that facilitates these steps by offering ways to decouple and independently tune the signal output as well as the response window. Our approach utilizes a dynamic DNA origami nanostructure to engineer a high optical signal response based on fluorescence resonance energy transfer. We demonstrate mechanisms to tune the sensor's response window, specificity and cooperativity as well as highlight the modularity of the proposed platform by extending it to different biomolecular targets including more complex sensing schemes. This versatile nanosensor platform offers a promising starting point for the rapid development of biosensors with tailored properties., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Augmented reality for laparoscopic liver resection is a visualisation mode that allows a surgeon to localise tumours and vessels embedded within the liver by projecting them on top of a laparoscopic image. Preoperative 3D models extracted from Computed Tomography (CT) or Magnetic Resonance (MR) imaging data are registered to the intraoperative laparoscopic images during this process. Regarding 3D-2D fusion, most algorithms use anatomical landmarks to guide registration, such as the liver's inferior ridge, the falciform ligament, and the occluding contours. These are usually marked by hand in both the laparoscopic image and the 3D model, which is time-consuming and prone to error. Therefore, there is a need to automate this process so that augmented reality can be used effectively in the operating room. We present the Preoperative-to-Intraoperative Laparoscopic Fusion challenge (P2ILF), held during the Medical Image Computing and Computer Assisted Intervention (MICCAI 2022) conference, which investigates the possibilities of detecting these landmarks automatically and using them in registration. The challenge was divided into two tasks: (1) A 2D and 3D landmark segmentation task and (2) a 3D-2D registration task. The teams were provided with training data consisting of 167 laparoscopic images and 9 preoperative 3D models from 9 patients, with the corresponding 2D and 3D landmark annotations. A total of 6 teams from 4 countries participated in the challenge, whose results were assessed for each task independently. All the teams proposed deep learning-based methods for the 2D and 3D landmark segmentation tasks and differentiable rendering-based methods for the registration task. The proposed methods were evaluated on 16 test images and 2 preoperative 3D models from 2 patients. In Task 1, the teams were able to segment most of the 2D landmarks, while the 3D landmarks showed to be more challenging to segment. In Task 2, only one team obtained acceptable qualitative and quantitative registration results. Based on the experimental outcomes, we propose three key hypotheses that determine current limitations and future directions for research in this domain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Mongolia is a country with a quickly growing economy mainly based on the mining of gold, copper, coal, and other minerals. Mining, urbanization, and agriculture impact the water quality in the upper Selenga River basin in northern Mongolia, which is the center of the Mongolian economy. Previous measurements of pollution loads were alarming, but restricted to chemical measurements. Here, for the first time, we combine freshwater biomonitoring and laboratory water quality data across a broad gradient of water quality and land use intensity. We track the effects of different types of pollution on aquatic invertebrates and test their use as bioindicators. We collected water samples, environmental parameters, and macroinvertebrates at 36 sampling sites at the rivers of Tuul, Kharaa, and Orkhon and their tributaries Sugnugur, Boroo, Sharyn Gol, Gatsuurt, and Yeröö. PCA of catchment water quality distinguished three groups of pollutants prevalent at the sites, (1) nutrients, (2) salt ions (Cl - , Na + , Mg 2+ , So 4 2- , Ca 2+ ) and mining by-products (B, Sr, U, Mo), and (3) (heavy) metals, which often exceeded regulatory standards. We recorded a total of 59 macroinvertebrate taxa belonging to 31 families in seven insect orders plus Amphipoda and Gastropoda. Species diversity declined with higher impact. Five environmental factors structured macroinvertebrate community composition in RDA: elevation of sample location, site total nitrogen, dissolved oxygen, electrical conductivity, and water chemistry. We conclude that macroinvertebrate communities are an appropriate and inexpensive tool for monitoring water quality in Mongolia and suggest government action to establish a long-term monitoring program., (© 2024. The Author(s).)

The flexible acquisition of substrates from nutrient pools is critical for microbes to prevail in competitive environments. To acquire glucose from diverse glycoside and disaccharide substrates, many free-living and symbiotic bacteria have developed, alongside hydrolysis, a non-hydrolytic pathway comprised of four biochemical steps and conferred from a single glycoside utilization gene locus (GUL). Mechanistically, this pathway integrates within the framework of oxidation and reduction at the glucosyl/glucose C3, the eliminative cleavage of the glycosidic bond and the addition of water in two consecutive lyase-catalyzed reactions. Here, based on study of enzymes from the phytopathogen Agrobacterium tumefaciens, we reveal a conserved Mn 2+ metallocenter active site in both lyases and identify the structural requirements for specific catalysis to elimination of 3-keto-glucosides and water addition to the resulting 2-hydroxy-3-keto-glycal product, yielding 3-keto-glucose. Extending our search of GUL-encoded putative lyases to the human gut commensal Bacteroides thetaiotaomicron, we discover a Ca 2+ metallocenter active site in a putative glycoside hydrolase-like protein and demonstrate its catalytic function in the eliminative cleavage of 3-keto-glucosides of opposite (α) anomeric configuration as preferred by the A. tumefaciens enzyme (β). Structural and biochemical comparisons reveal the molecular-mechanistic origin of 3-keto-glucoside lyase stereo-complementarity. Our findings identify a basic set of GUL-encoded lyases for glucoside metabolism and assign physiological significance to GUL genetic diversity in the bacterial domain of life., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Aims: Interatrial shunts are under evaluation as a treatment for heart failure (HF); however, their in vivo flow performance has not been quantitatively studied. We aimed to investigate the fluid dynamics properties of the 0.51 cm orifice diameter Ventura shunt and assess its lumen integrity with serial transesophageal echocardiography (TEE)., Methods and Results: Computational fluid dynamics (CFD) and bench flow tests were used to establish the flow-pressure relationship of the shunt. Open-label patients from the RELIEVE-HF trial underwent TEE at shunt implant and at 6 and 12 month follow-up. Shunt effective diameter (D eff ) was derived from the vena contracta, and flow was determined by the continuity equation. CFD and bench studies independently validated that the shunt's discharge coefficient was 0.88 to 0.89. The device was successfully implanted in all 97 enrolled patients; mean age was 70 ± 11 years, 97% were NYHA class III, and 51% had LVEF ≤40%. Patency was confirmed in all instances, except for one stenotic shunt at 6 months. D eff remained unchanged from baseline at 12 months (0.47 ± 0.01 cm, P = 0.376), as did the trans-shunt mean pressure gradient (5.1 ± 3.9 mmHg, P = 0.316) and flow (1137 ± 463 mL/min, P = 0.384). TEE measured flow versus pressure closely correlated (R 2  ≥ 0.98) with a fluid dynamics model. At 12 months, the pulmonary/systemic flow Qp/Qs ratio was 1.22 ± 0.12., Conclusions: When implanted in patients with advanced HF, this small interatrial shunt demonstrated predictable and durable patency and performance., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The unconventional superconductor CeRh_{2}As_{2} (critical temperature T_{c}≈0.4  K) displays an exceptionally rare magnetic-field-induced transition between two distinct superconducting (SC) phases, proposed to be states of even and odd parity of the SC order parameter, which are enabled by a locally noncentrosymmetric structure. The superconductivity is preceded by a phase transition of unknown origin at T_{0}=0.5  K. Electronic low-temperature properties of CeRh_{2}As_{2} show pronounced non-Fermi-liquid behavior, indicative of a proximity to a quantum critical point (QCP). The role of quantum fluctuations and normal state orders for the superconductivity in a system with staggered Rashba interaction is currently an open question, pertinent to explaining the occurrence of the two-phase superconductivity. In this work, using measurements of resistivity and specific heat under hydrostatic pressure, we show that the T_{0} order vanishes completely at a modest pressure of P_{0}≈0.5  GPa, revealing a QCP. In line with the quantum criticality picture, the linear temperature dependence of the resistivity at P_{0} evolves into a Fermi-liquid quadratic dependence as quantum critical fluctuations are suppressed by increasing pressure. Furthermore, the domelike behavior of T_{c} around P_{0} implies that the fluctuations of the T_{0} order are involved in the SC pairing mechanism.

ConspectusA rational design of catalysts requires a knowledge of the active species and sites. Often, catalyst surfaces are dominated by spectators, which do not participate in the reaction, while the catalytically active species and sites are hidden. Modulation-excitation spectroscopy (MES) allows discrimination between active and spectator species by applying a concentration modulation, which is translated into the active (that is, actively responding) species by phase-sensitive detection (PSD).While MES has been known for a while, its combination with infrared spectroscopy (IR-MES) has been applied to the detailed mechanistic analysis of a wide range of supported metal and metal oxide catalysts only recently, used for catalytic reactions such as CO 2 hydrogenation, water-gas shift, and CO and selective oxidation. The applicability of IR-MES is not limited to catalysis but has started to expand into other areas of research (e.g., gas sensing).In the context of renewable energy, CO 2 hydrogenation has been a matter of intense mechanistic debate, despite its great importance for synthesis gas production and further processing to fuels and chemicals. Applying IR-MES to supported Cu and Au catalysts enabled us to discriminate between redox and associative mechanisms. While CO 2 hydrogenation to CO and water follows an associative pathway with sequential H 2 activation via hydrides and formation of carbon- and oxygen-containing intermediates, such as carbonates and formates, the reverse reaction, that is, the water-gas shift reaction, was shown to proceed via a redox mechanism including oxygen vacancy formation followed by reoxidation of the catalyst by CO 2 .Recent IR-MES studies on (supported) metal oxides have provided direct spectroscopic insight into the catalytically active sites during the selective oxidation of alkanes and alcohols. By further expanding the potential of IR-MES by transient isotopic exchange experiments, we were able to resolve the nuclearity-dependent vanadium and adsorbate dynamics of supported vanadia catalysts during oxidative dehydrogenation, highlighting the intimate interplay between the surface vanadia species and the support. The strong influence of the support material (ceria and titania) on the sequence of reaction steps provides an explanation for the different catalytic performance. Based on these mechanistic insights, the rational design of improved catalysts has been possible.Expanding the application of IR-MES to the area of gas sensing, as recently demonstrated for doped SnO 2 , provides access to enhanced mechanistic insight, including previously undetected surface species. Methodical challenges arising from background features associated with semiconductor metal oxides have been successfully tackled, supporting further expansion of IR-MES in the gas sensing community. Mechanistically, the application of IR-MES allows identification of the actively participating OH groups and adsorbed species (e.g., alkoxy, CO, carbonate) and monitoring of reaction sequences based on their temporal behavior, providing a level of understanding typically not accessible by steady-state methods.As outlined above, the combination of MES/PSD with IR spectroscopy constitutes a powerful approach for the identification of catalytically active species and sites, which is essential for a profound mechanistic understanding of surface reactions, greatly facilitating the rational design of catalysts and other functional materials.

Allostery is a hallmark of cellular function and important in every biological system. Still, we are only starting to mimic it in the laboratory. Here, we introduce an approach to study aspects of allostery in artificial systems. We use a DNA origami domino array structure which-upon binding of trigger DNA strands-undergoes a stepwise allosteric conformational change. Using two FRET probes placed at specific positions in the DNA origami, we zoom in into single steps of this reaction cascade. Most of the steps are strongly coupled temporally and occur simultaneously. Introduction of activation energy barriers between different intermediate states alters this coupling and induces a time delay. We then apply these approaches to release a cargo DNA strand at a predefined step in the reaction cascade to demonstrate the applicability of this concept in tunable cascades of mechanochemical coupling with both spatial and temporal control., (© 2024. The Author(s).)

Background: Extracts of oleogum resins of Boswellia trees possess anti-inflammatory activities. Micellar formulations have been developed to increase the oral bioavailability of bioactive boswellic and lupeolic acids., Purpose: The current single-dose crossover clinical trial compares for the first time pharmacokinetics/pharmacodynamics of two Boswellia serrata nutraceuticals, native Biotikon® BS-85 and micellar Boswellia-Loges®., Methods: After oral administration of the study preparations (800 mg) to 20 healthy volunteers, plasma concentrations of 8 boswellic and lupeolic acids were measured by using HPLC-MS/MS for up to 48 h Blood samples collected 2 and 5 h after drug administration were stimulated for 24 h with endotoxic lipopolysaccharide. The release of proinflammatory cytokines analyzed by flow cytometry was used as readout of the pharmacodynamic properties of the preparations., Registration: German Clinical Trials Register (DRKS) No. DRKS00027369., Results: Administration of the micellar extract significantly increased C max, AUC 0-48 , and shortened T max for all boswellic and lupeolic acids compared to native extract. Accordingly, their relative bioavailability increased to 1,720-4,291 % with the highest difference for acetyl-11-keto-β-boswellic acid (AKBA). Both preparations reduced the release of TNF-α and the native formulation diminished also IL-1β and IL-6. However, no significant differences were observed between the preparations, except for a higher decrease in IL-1β by the native formulation Biotikon® BS-85. In a lymphocytic gene reporter cell line, both nutraceuticals similarly inhibited the NF-κB transcription factor activity as well as the TNF-α release, yet the native formulation Biotikon®BS-85 was more efficient in inhibiting TNF-α., Conclusion: Administration of the micellar Boswellia serrata nutraceutical increased the oral bioavailability of boswellic and lupeolic acids. Yet, the increase in plasma concentration did not enhance the anti-inflammatory efficacy of the micellar extract compared to the native extract in this ex vivo model., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Reflectance-based oxygen consumption measurement utilizes changes in oxymyoglobin levels between bloomed and vacuum-packaged meat, assuming that oxymyoglobin is converted to deoxymyoglobin. However, the interconversion of oxymyoglobin to deoxymyoglobin depends on the age of the meat and the length of display; hence, oxygen consumption calculations might yield inaccurate interpretations if deoxymyoglobin is not the final form. The objective was to evaluate the effectiveness of determining metmyoglobin levels during oxygen consumption analysis and its relationship to beef color stability. Seven psoas major (color labile) and longissimus (color stable) were displayed in retail for 6 d and evaluated for oxygen consumption on the retail (oxygen exposed) and interior (non‑oxygen exposed) surfaces. The retail surface had greater (P < 0.05) metmyoglobin formed during oxygen consumption than the interior surface on d 6 of the display. Furthermore, the psoas major muscle exhibited greater (P < 0.05) metmyoglobin content during oxygen consumption than the longissimus on the retail surface paralleling with the decline in color stability. Therefore, the study indicates that sampling location and including metmyoglobin content in oxygen consumption calculations, along with changes in oxymyoglobin, will better explain meat color stability., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Energy transitions are knowledge-intensive processes where a multitude of actors are trying to cope with inevitable knowledge gaps, surprises, and uncertainties. In this context, we focus on two techno-physical phenomena that are gaining practical relevance with the expansion of wind and geothermal energy extraction, and are surrounded by significant unknowns: wake effects and temperature plumes. Both phenomena can potentially affect the efficiency of energy production, but the extent of their impact is not yet known. Based on 28 semi-structured interviews with experts in the fields of wind and geothermal energy, we explore how different central actors perceive and interpret non-knowledge of wake effects and temperature plumes, and how they deal with it. We show that there are strategies for either using non-knowledge as a basis for action or simply ignoring it and sweeping knowledge gaps under the rug. Both strategies serve the function of protecting agency and keeping things going.

A major challenge in image-guided laparoscopic surgery is that structures of interest often deform and go, even if only momentarily, out of view. Methods which rely on having an up-to-date impression of those structures, such as registration or localisation, are undermined in these circumstances. This is particularly true for soft-tissue structures that continually change shape - in registration, they must often be re-mapped. Furthermore, methods which require 'revisiting' of previously seen areas cannot in principle function reliably in dynamic contexts, drastically weakening their uptake in the operating room. We present a novel approach for learning to estimate the deformed states of previously seen soft tissue surfaces from currently observable regions, using a combined approach that includes a Graph Neural Network (GNN). The training data is based on stereo laparoscopic surgery videos, generated semi-automatically with minimal labelling effort. Trackable segments are first identified using a feature detection algorithm, from which surface meshes are produced using depth estimation and delaunay triangulation. We show the method can predict the displacements of previously visible soft tissue structures connected to currently visible regions with observed displacements, both on our own data and porcine data. Our innovative approach learns to compensate non-rigidity in abdominal endoscopic scenes directly from stereo laparoscopic videos through targeting a new problem formulation, and stands to benefit a variety of target applications in dynamic environments. Project page for this work: https://gitlab.com/nct&#95;tso&#95;public/seesaw-soft-tissue-deformation.

Limited studies have determined the effects of modified atmospheric packaging (MAP) on atypical dark-cutting beef surface color. The objective was to compare the impacts of using vacuum packaging, carbon monoxide (CO-MAP), and HiOx-MAP (high‑oxygen) on the retail color of normal-pH and atypical dark-cutting beef aged 14 d. Atypical dark-cutting beef (pH 5.63) had numerically greater (P > 0.05) pH than normal-pH beef (pH 5.56). Atypical dark-cutting steaks were darker in color (lower L* values; P < 0.05) than normal-pH steaks. Atypical dark-cutting steaks had greater (P < 0.05) oxygen consumption, lower (P < 0.05) relative oxygenation, and less inter-muscle bundle space (P < 0.05) than normal-pH steaks. There were no differences (P > 0.05) in redness between normal-pH and atypical dark-cutting steaks when packaged in HiOx-MAP. Although a minimal increase in pH was observed in atypical dark-cutting beef, steaks in CO-MAP had lower redness than normal-pH steaks., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Ltd.)

Human brain activity consists of different frequency bands associated with varying functions. Oscillatory activity of frontal brain regions in the theta range (4-8 Hz) is linked to cognitive processing and can be modulated by neurofeedback - a technique where participants receive real-time feedback about their brain activity and learn to modulate it. However, criticism of this technique evolved, and high heterogeneity of study designs complicates a valid evaluation of its effectiveness. This meta-analysis provides the first systematic overview over studies attempting to modulate frontal midline theta with neurofeedback in healthy human participants. Out of 1261 articles screened, 14 studies were eligible for systematic review and 11 for quantitative meta-analyses. Studies were evaluated following the DIAD model and the PRISMA guidelines. A significant across-study effect of medium size (Hedges' g = .66; 95%-CI [-0.62, 1.73]) with substantial between-study heterogeneity (Q(16) = 167.43, p < .001) was observed and subanalysis revealed effective frontal midline theta upregulation. We discuss moderators of effect sizes and provide guidelines for future research in this dynamic field., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Here we report the efficient synthetic access to 13 C/ 15 N-labelled pseudouridine phosphoramidites, which were incorporated into a binary H/ACA box guide RNA/product complex comprising 77 nucleotides (nts) in total and into a 75 nt E. coli tRNA Gly . The stable isotope (SI) labelled pseudouridines were produced via a highly efficient chemo-enzymatic synthesis. 13 C/ 15 N labelled uracils were produced via chemical synthesis and enzymatically converted to pseudouridine 5'-monophosphate (ΨMP) by using YeiN, a Ψ-5'-monophosphate C-glycosidase. Removal of the 5'-phosphate group yielded the desired pseudouridine nucleoside (Ψ), which was transformed into a phosphoramidite building suitable for RNA solid phase synthesis. A Ψ -building block carrying both a 13 C and a 15 N label was incorporated into a product RNA and the complex formation with a 63 nt H/ACA box RNA could be observed via NMR. Furthermore, the SI labelled pseudouridine building block was used to determine imino proton bulk water exchange rates of a 75 nt E. coli tRNA Gly CCmnm 5 U, identifying the TΨC-loop 5-methyluridine as a modifier of the exchange rates. The efficient synthetic access to SI-labelled Ψ building blocks will allow the solution and solid-state NMR spectroscopic studies of Ψ containing RNAs and will facilitate the mass spectrometric analysis of Ψ-modified nucleic acids., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Brain-computer interfaces (BCIs) are scientifically well established, but they rarely arrive in the daily lives of potential end-users. This could be in part because electroencephalography (EEG), a prevalent method to acquire brain activity for BCI operation, is considered too impractical to be applied in daily life of end-users with physical impairment as an assistive device. Hence, miniaturized EEG systems such as the cEEGrid have been developed. While they promise to be a step toward bridging the gap between BCI development, lab demonstrations, and home use, they still require further validation. Encouragingly, the cEEGrid has already demonstrated its ability to record visually and auditorily evoked event-related potentials (ERP), which are important as input signal for many BCIs. With this study, we aimed at evaluating the cEEGrid in the context of a BCI based on tactually evoked ERPs. To compare the cEEGrid with a conventional scalp EEG, we recorded brain activity with both systems simultaneously. Forty healthy participants were recruited to perform a P300 oddball task based on vibrotactile stimulation at four different positions. This tactile paradigm has been shown to be feasible for BCI repeatedly but has never been tested with the cEEGrid. We found distinct P300 deflections in the cEEGrid data, particularly at vertical bipolar channels. With an average of 63%, the cEEGrid classification accuracy was significantly above the chance level (25%) but significantly lower than the 81% reached with the EEG cap. Likewise, the P300 amplitude was significantly lower (cEEGrid R2-R7: 1.87 μV, Cap Cz: 3.53 μV). These results indicate that a tactile BCI using the cEEGrid could potentially be operated, albeit with lower efficiency. Additionally, participants' somatosensory sensitivity was assessed, but no correlation to the accuracy of either EEG system was shown. Our research contributes to the growing amount of literature comparing the cEEGrid to conventional EEG systems and provides first evidence that the tactile P300 can be recorded behind the ear. A BCI based on a thus simplified EEG system might be more readily accepted by potential end-users, provided the accuracy can be substantially increased, e.g., by training and improved classification., 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., (Copyright © 2024 Eidel, Pfeiffer, Ziebell and Kübler.)

Cerebral cavernous malformation (CCM) has variable clinical symptoms, including potentially fatal hemorrhagic stroke. Treatment options are very limited, presenting a large unmet need. REC-994 (also known as tempol), identified as a potential treatment through an unbiased drug discovery platform, is hypothesized to treat CCMs through a reduction in superoxide, a reactive oxygen species. We investigated the safety, tolerability, and pharmacokinetic profile of REC-994 in healthy volunteers. Single- and multiple-ascending dose (SAD and MAD, respectively) studies were conducted in adult volunteers (ages 18-55). SAD study participants received an oral dose of REC-994 or placebo. MAD study participants were randomized 3:1 to oral doses of REC-994 or matching placebo, once daily for 10 days. Thirty-two healthy volunteers participated in the SAD study and 52 in the MAD study. Systemic exposure increased in proportion to REC-994 dose after single doses of 50-800 mg and after 10 days of dosing over the 16-fold dose range of 50-800 mg. Median T max and mean t 1/2 were independent of dose in both studies, and the solution formulation was more rapidly absorbed. REC-994 was well tolerated. Treatment-emergent adverse effects across both studies were mild and transient and resolved by the end of the study. REC-994 has a favorable safety profile and was well tolerated in single and multiple doses up to 800 mg with no dose-limiting adverse effects identified. Data support conducting a phase 2 clinical trial in patients with symptomatic CCM., (© 2024 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Purpose: In surgical computer vision applications, data privacy and expert annotation challenges impede the acquisition of labeled training data. Unpaired image-to-image translation techniques have been explored to automatically generate annotated datasets by translating synthetic images into a realistic domain. The preservation of structure and semantic consistency, i.e., per-class distribution during translation, poses a significant challenge, particularly in cases of semantic distributional mismatch., Method: This study empirically investigates various translation methods for generating data in surgical applications, explicitly focusing on semantic consistency. Through our analysis, we introduce a novel and simple combination of effective approaches, which we call ConStructS. The defined losses within this approach operate on multiple image patches and spatial resolutions during translation., Results: Various state-of-the-art models were extensively evaluated on two challenging surgical datasets. With two different evaluation schemes, the semantic consistency and the usefulness of the translated images on downstream semantic segmentation tasks were evaluated. The results demonstrate the effectiveness of the ConStructS method in minimizing semantic distortion, with images generated by this model showing superior utility for downstream training., Conclusion: In this study, we tackle semantic inconsistency in unpaired image translation for surgical applications with minimal labeled data. The simple model (ConStructS) enhances consistency during translation and serves as a practical way of generating fully labeled and semantically consistent datasets at minimal cost. Our code is available at https://gitlab.com/nct&#95;tso&#95;public/constructs ., (© 2024. The Author(s).)

Acute graft-versus-host disease (aGVHD) remains a barrier to successful allogeneic hematopoietic stem cell transplantation (HSCT) outcomes. Contemporary comprehensive analyses of real-world clinical outcomes among patients who develop aGVHD post-HSCT are needed to better understand the unmet needs of this patient population. This multicenter, retrospective chart review describes treatment patterns and clinical outcomes among patients (≥18 years old) from Finland, Sweden, and France who developed grades II-IV aGVHD after their first HSCT (January 2016-June 2017). From 13 participating centers, 151 patients were included. The median (Q1, Q3) age at HSCT was 56 (45, 62) years old. One line of aGVHD treatment was received by 47.7%, and the most common first-line treatment was methylprednisolone (alone or in a combination regimen, 74.2%; monotherapy, 25.8%). Among patients treated with methylprednisolone, 79.5% achieved a complete or partial response. The median (Q1, Q3) number of treatment lines was 2.0 (1.0, 3.0). The median (Q1, Q3) time to obtain an aGVHD diagnosis from transplant was 29.5 (21.0, 44.0) days, and 14.5 (7.0, 34.0) days to achieve the best response for 110 evaluable patients. At 6 and 12 months, 53.6% and 49.0%, respectively, achieved a complete response. Chronic GVHD occurred in 37.7% of patients, and aGVHD reoccurred in 26.5%. Following aGVHD diagnosis, mortality rates were 30.0% at 6 months and 37.3% at 12 months. Findings from this study demonstrate a continuing unmet need for new therapies that control aGVHD and improve mortality.

Objective: Evaluation of the benefits of a virtual reality (VR) environment with a head-mounted display (HMD) for decision-making in liver surgery., Background: Training in liver surgery involves appraising radiologic images and considering the patient's clinical information. Accurate assessment of 2D-tomography images is complex and requires considerable experience, and often the images are divorced from the clinical information. We present a comprehensive and interactive tool for visualizing operation planning data in a VR environment using a head-mounted-display and compare it to 3D visualization and 2D-tomography., Methods: Ninety medical students were randomized into three groups (1:1:1 ratio). All participants analyzed three liver surgery patient cases with increasing difficulty. The cases were analyzed using 2D-tomography data (group "2D"), a 3D visualization on a 2D display (group "3D") or within a VR environment (group "VR"). The VR environment was displayed using the "Oculus Rift ™" HMD technology. Participants answered 11 questions on anatomy, tumor involvement and surgical decision-making and 18 evaluative questions (Likert scale)., Results: Sum of correct answers were significantly higher in the 3D (7.1 ± 1.4, p < 0.001) and VR (7.1 ± 1.4, p < 0.001) groups than the 2D group (5.4 ± 1.4) while there was no difference between 3D and VR (p = 0.987). Times to answer in the 3D (6:44 ± 02:22 min, p < 0.001) and VR (6:24 ± 02:43 min, p < 0.001) groups were significantly faster than the 2D group (09:13 ± 03:10 min) while there was no difference between 3D and VR (p = 0.419). The VR environment was evaluated as most useful for identification of anatomic anomalies, risk and target structures and for the transfer of anatomical and pathological information to the intraoperative situation in the questionnaire., Conclusions: A VR environment with 3D visualization using a HMD is useful as a surgical training tool to accurately and quickly determine liver anatomy and tumor involvement in surgery., (© 2024. The Author(s).)

Introduction: The medical development in the previous 15 years and the changes in treatment reality of the comprehensive elective treatment of abdominal aortic aneurysms necessitate a re-evaluation of the quality assurance guidelines of the Federal Joint Committee in Germany (QBAA-RL). In the current version this requires a specialist further training quota for nursing personnel in intensive care wards of 50%. The quota was determined in 2008 based on expert opinions, although a direct empirical evidence base for this does not exist., Methods: Representatives from the fields of patient representation, physicians, nursing personnel and other relevant interface areas were invited to participate in a modified Delphi procedure. Following a comprehensive narrative literature search, a survey and focus group discussions with national and international experts, a total of three anonymized online-based voting rounds were carried out for which previously determined key statements were assessed with a 4‑point Likert scale (totally disagree up to totally agree). In addition, the expert panel had also defined a recommendation for a minimum quota for the specialist training of nursing personnel on intensive care wards in the treatment of abdominal aortic aneurysms, whereby an a priori agreement of 80% of the participants was defined as the consensus limit., Results: Overall, 37 experts participated in the discussions and three successive voting rounds (participation rate 89%). The panel confirmed the necessity of a re-evaluation of the guideline recommendations and recommended the introduction of a shift-related minimum quota of 30% of the full-time equivalent of nursing personnel on intensive care wards and the introduction of structured promotional programs for long-term elevation of the quota., Conclusion: In this national Delphi procedure with medical and nursing experts as well as representatives of patients, the fundamental benefits and needs of professional specialist qualifications in the field of intensive care medicine were confirmed. The corresponding minimum quota for specialist further training of intensive care nursing personnel should generally apply without limitations to specific groups. The expert panel stipulates a shift-related minimum quota for intensive care nursing personnel with specialist training of 30% of the nursing personnel on intensive care wards and the obligatory introduction of structured and transparent promotion programs for the long-term enhancement., (© 2024. The Author(s).)

Meat discoloration starts at the interface between the bright red oxymyoglobin layer and the interior deoxymyoglobin layer. Currently, limited tools are available to characterize myoglobin forms formed within the sub-surface of meat. The objective was to demonstrate a needle-probe based single-fiber reflectance (SfR) spectroscopy approach for characterizing sub-surface myoglobin forms of beef psoas major muscles during retail storage. A 400-μm fiber was placed in a 17-gauge needle, and the assembly was inserted into the muscle at five depths of 1 mm increment and 1 cm lateral shift. Metmyoglobin content increased at all depths during display and content at 1 mm was greater compared to that of 2 to 5 mm depth. The a* values decreased (P < 0.05) during retail display aligning with the sub-surface formation of metmyoglobin. In summary, the results suggest that needle-probe SfR spectroscopy can determine interior myoglobin forms and characterize meat discoloration., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Aims: Heart failure (HF) outcomes remain poor despite optimal guideline-directed medical therapy (GDMT). We assessed safety, effectiveness, and transthoracic echocardiographic (TTE) outcomes during the 12 months after Ventura shunt implantation in the RELIEVE-HF open-label roll-in cohort., Methods and Results: Eligibility required symptomatic HF despite optimal GDMT with ≥1 HF hospitalization in the prior year or elevated natriuretic peptides. The safety endpoint was device-related major adverse cardiovascular or neurological events at 30 days, compared to a prespecified performance goal. Effectiveness evaluations included the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline, 1, 3, 6, and 12 months and TTE at baseline and 12 months. Overall, 97 patients were enrolled and implanted at 64 sites. Average age was 70 ± 11 years, 97% were in New York Heart Association class III, and half had left ventricular ejection fraction (LVEF) ≤40%. The safety endpoint was achieved (event rate 0%, p < 0.001). KCCQ overall summary score was improved by 12-16 points at all follow-up timepoints (all p < 0.004), with similar outcomes in patients with reduced and preserved LVEF. At 12 months, left ventricular end-systolic and end-diastolic volumes were reduced (p = 0.020 and p = 0.038, respectively), LVEF improved (p = 0.009), right ventricular end-systolic and end-diastolic areas were reduced (p = 0.001 and p = 0.030, respectively), and right ventricular fractional area change (p < 0.001) and tricuspid annular plane systolic excursion (p < 0.001) improved., Conclusion: Interatrial shunting with the Ventura device was safe and resulted in favourable clinical effects in patients with HF, regardless of LVEF. Improvements of left and right ventricular structure and function were consistent with reverse myocardial remodelling. These results would support the potential of this shunt device as a treatment for HF., (© 2024 European Society of Cardiology.)

Background: Right ventricular (RV) systolic dysfunction has been identified as a prognostic marker for adverse clinical events in patients presenting with acute pulmonary embolism (PE). However, challenges exist in identifying RV dysfunction using conventional echocardiography techniques. Strain echocardiography is an evolving imaging modality which measures myocardial deformation and can be used as an objective index of RV systolic function. This study evaluated RV Global Longitudinal Strain (RVGLS) in patients with intermediate risk PE as a parameter of RV dysfunction, and compared to traditional echocardiographic and CT parameters evaluating short-term mortality., Methods: Retrospective single center cohort study of 251 patients with intermediate-risk PE between 2010 and 2018. The primary outcome was all-cause mortality at 30 days. Statistical analysis evaluated each parameter comparing survivors versus non-survivors at 30 days. Receiver operating characteristic (ROC) curves and Kaplan-Meier curves were used for comparison of the two cohorts., Results: Altogether 251 patients were evaluated. Overall mortality rate was 12.4%. Utilizing an ROC curve, an absolute cutoff value of 17.7 for RVGLS demonstrated a sensitivity of 93% and specificity of 70% for observed 30-day mortality. Individuals with an RVGLS ≤17.7 had a 25 times higher mortality rate than those with RVGLS above 17.7 (HR 25.24, 95% CI = 6.0-106.4, p < .001). Area under the curve was (.855), RVGLS outperformed traditional echocardiographic parameters, CT findings, and cardiac biomarkers on univariable and multivariable analysis., Conclusions: Reduced RVGLS values on initial echocardiographic assessment of patients with intermediate-risk PE identified patients at higher risk for mortality at 30 days., (© 2024 The Authors. Echocardiography published by Wiley Periodicals LLC.)

The lack of affordable and effective therapeutics against cognitive impairment has promoted research toward alternative approaches to the treatment of neurodegeneration. In recent years, a bidirectional pathway that allows the gut to communicate with the central nervous system has been recognized as the gut-brain axis. Alterations in the gut microbiota, a dynamic population of trillions of microorganisms residing in the gastrointestinal tract, have been implicated in a variety of pathological states, including neurodegenerative disorders such as Alzheimer's disease (AD). However, probiotic treatment as an affordable and accessible adjuvant therapy for the correction of dysbiosis in AD has not been thoroughly explored. Here, we sought to correct the dysbiosis in an AD mouse model with probiotic supplementation, with the intent of exploring its effects on disease progression. Transgenic 3xTg-AD mice were fed a control or a probiotic diet ( Lactobacillus plantarum KY1032 and Lactobacillus curvatus HY7601 ) for 12  weeks, with the latter leading to a significant increase in the relative abundance of Bacteroidetes . Cognitive functions were evaluated via Barnes Maze trials and improvements in memory performance were detected in probiotic-fed AD mice. Neural tissue analysis of the entorhinal cortex and hippocampus of 10-month-old 3xTg-AD mice demonstrated that astrocytic and microglial densities were reduced in AD mice supplemented with a probiotic diet, with changes more pronounced in probiotic-fed female mice. In addition, elevated numbers of neurons in the hippocampus of probiotic-fed 3xTg-AD mice suggested neuroprotection induced by probiotic supplementation. Our results suggest that probiotic supplementation could be effective in delaying or mitigating early stages of neurodegeneration in the 3xTg-AD animal model. It is vital to explore new possibilities for palliative care for neurodegeneration, and probiotic supplementation could provide an inexpensive and easily implemented adjuvant clinical treatment for AD., 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., (Copyright © 2024 Medeiros, McMurry, Pfeiffer, Newsome, Testerman, Graf, Silver and Sacchetti.)

Objectives: Musculoskeletal ultrasound (MSUS) is increasingly used by rheumatologists in daily clinical practice. However, MSUS is only valuable in trained hands, and assessment of trainee competences is therefore essential before independent practice. Thus, this study aimed to establish validity evidence for the EULAR and the Objective Structured Assessment of Ultrasound Skills (OSAUS) tools used for assessing MSUS competences., Methods: Thirty physicians with different levels of MSUS experience (novices, intermediates, and experienced) performed four MSUS examinations of different joint areas on the same rheumatoid arthritis patient. All examinations were video recorded (n = 120), anonymized, and subsequently assessed in random order by two blinded raters using first the OSAUS assessment tool followed by the EULAR tool 1 month after., Results: The inter-rater reliability between the two raters was high for both the OSAUS and EULAR tools, with a Pearson correlation coefficient (PCC) of 0.807 and 0.848, respectively. Both tools demonstrated excellent inter-case reliability, with a Cronbach's alpha of 0.970 for OSAUS and 0.964 for EULAR. Furthermore, there was a strong linear correlation between the OSAUS and the EULAR performance scores and the participants' experience levels (R2 = 0.897 and R2 = 0.868, respectively) and a significant discrimination between different MSUS experience levels (P < 0.001 for both)., Conclusions: MSUS operator competences can be assessed reliably and valid using either the OSAUS or the EULAR assessment tool, thereby allowing a uniform competency-based MSUS education in the future. Although both tools demonstrated high inter-rater reliability, the EULAR tool was superior to OSAUS., Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT05256355., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Abstract: Juvenile fibromyalgia (JFM) is a chronic condition characterized by symptoms of pain and fatigue and is associated with sedentary behavior and functional disability. Adults with fibromyalgia exhibit deficits in physical fitness as evidenced by lower aerobic capacity and physical endurance, but it is unknown whether these impairments are apparent in adolescents with JFM. Furthermore, the extent to which functional disability and pain interference relate to measures of physical fitness has not been investigated in a pediatric pain population. During a baseline assessment for a clinical trial, 321 adolescents with juvenile fibromyalgia (M age = 15.14, 85.2% female) completed measures of pain intensity, fatigue, JFM symptom severity, functional disability, and pain interference. They also completed 2 validated fitness tasks: (1) the Harvard step test, which assesses aerobic fitness, and (2) the 6-minute walk test, a simple submaximal test of endurance. We examined associations among self-report measures and fitness assessments using bivariate correlations. We then employed hierarchical regression analyses to determine the unique contributions of physical fitness assessments to self-reported functional disability and pain interference. Results indicated that youth with JFM exhibited deficits in aerobic capacity and physical endurance. However, physical fitness explained negligible variance in functional disability and pain interference beyond that accounted for by pain, fatigue, and JFM symptom severity. Scores on available functional disability measures may reflect perceived difficulties in coping with symptoms during physical tasks rather than actual physical capability. Rigorous and sensitive assessments of physical fitness and endurance are needed to determine whether rehabilitation interventions for pediatric pain improve physical functioning., (Copyright © 2023 International Association for the Study of Pain.)

Endoscopic optical coherence tomography (OCT) offers a non-invasive approach to perform the morphological and functional assessment of the middle ear in vivo. However, interpreting such OCT images is challenging and time-consuming due to the shadowing of preceding structures. Deep neural networks have emerged as a promising tool to enhance this process in multiple aspects, including segmentation, classification, and registration. Nevertheless, the scarcity of annotated datasets of OCT middle ear images poses a significant hurdle to the performance of neural networks. We introduce the Dresden in vivo OCT Dataset of the Middle Ear (DIOME) featuring 43 OCT volumes from both healthy and pathological middle ears of 29 subjects. DIOME provides semantic segmentations of five crucial anatomical structures (tympanic membrane, malleus, incus, stapes and promontory), and sparse landmarks delineating the salient features of the structures. The availability of these data facilitates the training and evaluation of algorithms regarding various analysis tasks with middle ear OCT images, e.g. diagnostics., (© 2024. The Author(s).)

Objectives: Interventional musculoskeletal ultrasound (MSUS) procedures are routinely performed in rheumatology practice. However, the efficacy and safety of the procedures rely on the competence of the physician, and assessment of skills is crucial. Thus, this study aimed to develop and establish validity evidence for a tool assessing trainees' interventional MSUS skills., Methods: An expert panel of rheumatologists modified an existing tool for assessing competences in invasive abdominal and thoracic ultrasound procedures. The new tool (the Assessment of Interventional Musculoskeletal Ultrasound Skills (AIMUS) tool) reflects the essential steps in interventional MSUS. To establish validity evidence, physicians with different levels of interventional MSUS experience were enrolled and performed two procedures on a rubber fantom, simulating real patient cases. All performances were video recorded, anonymized, and assessed in random order by two blinded raters using the AIMUS tool., Results: Sixty-five physicians from 21 different countries were included and categorized into groups based on their experience, resulting in 130 videos for analysis. The internal consistency of the tool was excellent, with a Cronbach's alpha of 0.96. The inter-case reliability was good with a Pearson's correlation coefficient (PCC) of 0.74 and the inter-rater reliability was moderate to good (PCC 0.58). The ability to discriminate between different levels of experience was highly significant (p< 0.001)., Conclusions: We have developed and established validity evidence for a new interventional MSUS assessment tool. The tool can be applied in future competency-based educational programs, provide structured feedback to trainees in daily clinical practice, and ensure end-of-training competence., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background. Tricuspid regurgitation (TR) is a high-prevalence disease associated with poor quality of life and mortality. This quantitative patient preference study aims to identify TR patients' perspectives on risk-benefit tradeoffs. Methods. A discrete-choice experiment was developed to explore TR treatment risk-benefit tradeoffs. Attributes (levels) tested were treatment (procedure, medical management), reintervention risk (0%, 1%, 5%, 10%), medications over 2 y (none, reduce, same, increase), shortness of breath (none/mild, moderate, severe), and swelling (never, 3× per week, daily). A mixed logit regression model estimated preferences and calculated predicted probabilities. Relative attribute importance was calculated. Subgroup analyses were performed. Results. An online survey was completed by 150 TR patients. Shortness of breath was the most important attribute and accounted for 65.8% of treatment decision making. The average patients' predicted probability of preferring a "procedure-like" profile over a "medical management-like" profile was 99.7%. This decreased to 78.9% for a level change from severe to moderate in shortness of breath in the "medical management-like" profile. Subgroup analysis confirmed that patients older than 64 y had a stronger preference to avoid severe shortness of breath compared with younger patients ( P  < 0.02), as did severe or worse TR patients relative to moderate. New York Heart Association class I/II patients more strongly preferred to avoid procedural reintervention risk relative to class III/IV patients ( P  < 0.03). Conclusion. TR patients are willing to accept higher procedural reintervention risk if shortness of breath is alleviated. This risk tolerance is higher for older and more symptomatic patients. These results emphasize the appropriateness of developing TR therapies and the importance of addressing symptom burden., Highlights: This study provides quantitative patient preference data from clinically confirmed tricuspid regurgitation (TR) patients to understand their treatment preferences.Using a targeted literature search and patient, physician, and Food and Drug Administration feedback, a cross-sectional survey with a discrete-choice experiment that focused on 5 of the most important attributes to TR patients was developed and administered online.TR patients are willing to accept higher procedural reintervention risk if shortness of breath is alleviated, and this risk tolerance is higher for older and more symptomatic patients., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The external authors and study sponsors participated in study design, data collection, data analysis, data interpretation, and development of the manuscript and gave approval to submit for publication. Dr. Iyer has had a consulting relationship with Edwards Lifesciences, Medtronic, Abbott, and Boston Scientific. Dr. Wyler von Ballmoos has had a consulting relationship with Medtronic and Boston Scientific. Both Ms. Mollenkopf and Ms. Mancilla are employees of Edwards Lifesciences. Ms. Latibeaudiere-Gardner is an employee of ICON PLC, a consultancy contracted by Edwards Lifesciences. Dr. Reardon has a consulting relationship with Edwards Lifesciences and Medtronic. Financial support for this study was provided Edwards Lifesciences by a contract with ICON Clinical Research Limited. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report. The following authors are employed by the sponsor: Melissa Mancilla and Sarah Mollenkopf. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Edwards Lifesciences provided financial support for this research., (© The Author(s) 2024.)

Mongolia is a country with a quickly growing economy mainly based on mining of gold, copper, coal, and other minerals. Mining, urbanization, and agriculture impact the water quality in the upper Selenga River Basin in northern Mongolia, which is the center of the Mongolian economy. Previous measurements of pollution loads were alarming, but restricted to chemical measurements. Here, for the first time, we combine freshwater biomonitoring and laboratory water quality data across a broad gradient of water quality and land use intensity. We track the effects of different types of pollution on aquatic invertebrates and test their use as bioindicators. We collected water samples, environmental parameters, and macroinvertebrates at 36 sampling sites at the rivers of Tuul, Kharaa, and Orkhon and their tributaries Sugnugur, Boroo, Sharyn Gol, Gatsuurt, and Yeröö. PCA of catchment water quality distinguished three groups of pollutants prevalent at the sites: (1) nutrients, (2) saline components (Cl - , Na  + , Mg 2+ , SO 4 2- , Ca 2+ ) and mining by-products (B, Sr, U, Mo), and (3) (heavy) metals, which often exceeded regulatory standards. We recorded a total of 59 macroinvertebrate taxa belonging to 32 families in seven insect orders plus Amphipoda and Gastropoda. Species diversity declined with higher impact. Five environmental factors structured macroinvertebrate community composition in RDA: elevation of sample location, site total nitrogen, dissolved oxygen, electrical conductivity, and water chemistry. We conclude that macroinvertebrate communities are an appropriate and inexpensive tool for monitoring water quality in Mongolia and suggest government action to establish a long-term monitoring program., (© 2023. The Author(s).)

Biological degradation of natural product glycosides involves, alongside hydrolysis, β-elimination for glycosidic bond cleavage. Here, we discover an O-glycoside β-eliminase (OGE) from Agrobacterium tumefaciens that converts the C3-oxidized O-β-D-glucoside of phloretin (a plant-derived flavonoid) into the aglycone and the 2-hydroxy-3-keto-glycal elimination product. While unrelated in sequence, OGE is structurally homologous to, and shows effectively the same Mn 2+ active site as, the C-glycoside deglycosylating enzyme (CGE) from a human intestinal bacterium implicated in β-elimination of 3-keto C-β-D-glucosides. We show that CGE catalyzes β-elimination of 3-keto O- and C-β-D-glucosides while OGE is specific for the O-glycoside substrate. Substrate comparisons and mutagenesis for CGE uncover positioning of aglycone for protonic assistance by the enzyme as critically important for C-glycoside cleavage. Collectively, our study suggests convergent evolution of active site for β-elimination of 3-keto O-β-D-glucosides. C-Glycoside cleavage is a specialized feature of this active site which is elicited by substrate through finely tuned enzyme-aglycone interactions., (© 2023. The Author(s).)

Background: Joint hypermobility is a common clinical finding amongst hereditary connective tissue disorders that is observed in pediatric rheumatological settings, and often associated with chronic pain. Joint hypermobility may also contribute to deficits in physical functioning and physical activity, but previous findings have been inconsistent. It is possible that physical activity impairment in joint hypermobility may be due to chronic aberrant movement patterns subsequent to increased joint laxity., Method: As part of a larger randomized pilot trial of juvenile onset fibromyalgia (JFM), a secondary analysis was conducted to explore whether adolescents with JFM and joint hypermobility differed from non-joint hypermobility peers in terms of pain, daily functioning, and biomechanics (i.e., kinetics and kinematics) during a moderately vigorous functional task., Results: From the larger sample of adolescents with JFM (N = 36), 13 adolescents (36.1%) met criteria for joint hypermobility and 23 did not have joint hypermobility. Those with joint hypermobility exhibited poorer overall functioning (Md = 20, Q 1 ,Q 3 [5.8, 7.6] vs. Md = 29, Q 1 ,Q 3 [5.1, 7.6]) but there were no differences in pain (Md = 6.9, Q 1 ,Q 3 [22, 33], vs. Md = 6.45, Q 1 ,Q 3 [15, 29.5]). Inspection of time-series plots suggests those with joint hypermobility exhibited decreased hip flexion and frontal plane hip moment (e.g., resistance to dynamic valgus) during the landing phase (early stance) and greater hip and knee transverse plane moments during the propulsion phase (late stance) of the drop vertical jump task (DVJ). No other differences in lower extremity biomechanics were observed between study groups., Conclusions: In this exploratory study, there were small but notable differences in biomechanics between patients with JFM who also had joint hypermobility versus those without joint hypermobility during a landing and jumping task (e.g., DVJ). These differences may indicate decreased joint stiffness during landing, associated with increased joint laxity and decreased joint stability, which may put them at greater risk for injury. Further study with a larger sample size is warranted to examine whether these biomechanical differences in patients with JFM and joint hypermobility affect their response to typical physical therapy or exercise recommendations., (© 2023. The Author(s).)

Objectives: To examine the effect of pre-course e-learning on residents' practical performance in musculoskeletal ultrasound (MSUS)., Methods: This was a multicentre, randomized controlled study following the Consolidated Standards of Reporting Trials (CONSORT) statement. Residents with no or little MSUS experience were randomized to either an e-learning group or a traditional group. One week before a 2-day face-to-face MSUS course, the e-learning group received access to an interactive platform consisting of online lectures, assignments, and practical instruction videos aligned with the content of the course. The traditional group only received standard pre-course information (program, venue, and time). All participants performed a pre- and post-course practical MSUS examination and were assessed by two individual raters, blinded to the group allocation, using the validated Objective Structured Assessment of Ultrasound Skills (OSAUS) tool., Results: Twenty-eight participants completed the study. There were no statistically significant differences in the pre- or post-course practical MSUS performance between the e-learning group and the traditional group; the mean pre-course OSAUS score (s.d.) in the -learning group was 5.4 (3.7) compared with 5.2 (2.4) in the traditional group (P = 0.8), whereas the post-course OSAUS score in the e-learning group was 11.1 (2.8) compared with 10.9 (2.4) in the traditional group (P = 0.8). There was a significant difference between the mean pre- and post-course scores (5.74 points, P < 0.001). The OSAUS assessment tool demonstrated good inter-rater reliability (intra-class correlation = 0.84)., Conclusion: We found no significant impact of pre-course e-learning on novices' acquisition of practical MSUS skills. Hands-on training is of the utmost importance and improves MSUS performance significantly. The OSAUS assessment tool is an applicable tool with high interrater reliability., Trial Registration: https://clinicaltrials.gov/ NCT04959162., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Selected patients with early-stage melanoma have a "hidden high risk" of poor oncologic outcomes. They might benefit from clinical trials, and ultimately, if warranted by trial results, judicious everyday use of adjuvant therapy. A promising tool to identify these individuals is the immunoprint ® assay. This immunohistochemical 7-biomarker prognostic test was clinically validated in three independent cohorts (N = 762) to classify early-stage patients as high-risk or low-risk regarding melanoma recurrence and mortality. Using College of American Pathologists (CAP) recommendations, we analytically validated this assay in primary melanoma specimens (N = 20 patients). We assessed assay precision by determining consistency of risk classification under repeated identical conditions (repeatability) or across varying conditions (reproducibility), involving separate assay runs, operators (laboratory scientists), and/or observers (e.g., dermatopathologists). Reference classification was followed by five analytical validation phases: intra-run/intra-operator, intra-observer, inter-run, inter-operator, and inter-observer. Concordance of classifications in each phase was assessed via Fleiss' kappa (primary endpoint) and percent agreement (secondary endpoint). Seven-marker signature classification demonstrated high consistency across validation categories (Fleiss' kappa 0.864-1.000; overall percent agreement 95-100%), in 9/10 cases, exceeding, and in 1/10 cases, closely approaching, CAP's recommended 0.9 level. The 7-marker assay has now been verified to provide excellent repeatability, reproducibility, and precision, besides having been clinically validated.

Phytochemical investigation of the two Tabernaemontana species (Apocynaceae) T . peduncularis Wall. and T . divaricata (L.) R.Br. ex Roem. & Schult. indicated closely related biosynthetic pathways leading to lipophilic and hydrophilic alkaloids. In total, 18 specialized metabolites comprising indole-derived alkaloid aglycones, three oxindole-derived alkaloid glycosides, and two iridoid glucosides could be identified in the studied species. Among the alkaloids, the two Iboga -type alkaloids 3,7-coronaridine isoindolenine, coronaridine 3,4-iminium and a javaniside derivative bearing a glucuronic acid, named javanuronic acid, could be described by spectroscopic and spectrometric methods for the first time. A docking experiment using alpha-fold was performed to generate a protein model of the enzyme 7-deoxyloganetic acid glucosyl transferase. Performed bioassays exhibited a growth reduction of neonate Spodoptera littoralis larvae and reduced cell viability of HepG2 cells of the extracts containing Iboga alkaloids, whilst the javaniside derivatives containing hydrophilic fraction did not show any effects. These findings indicate a high flexibility in the formation of bioactive indole alkaloid aglycones by Tabernaemontana species and also evidence similar accumulation trends in both species as well as indicate that biosynthetic routes leading to oxindole alkaloids like javanisides are more widespread than reported. Furthermore, the incorporation of the three novel compounds into potential biosynthetic pathways is discussed.

Objective: Dosing of tumour necrosis factor-α inhibitors (TNFis) is not personalized causing interindividual variation in serum drug levels; however, dose optimization is not widely implemented. We hypothesized that some patients are overdosed; thus, drug prescription could be reduced by therapeutic drug monitoring (TDM)., Method: Independent of disease activity, 239 adults treated for rheumatoid arthritis (n = 99), psoriatic arthritis 15 (n = 48), or spondyloarthritis (n = 92) were recruited for a 48-week prospective, randomized open-label trial. Standard care alone or plus TDM was applied in chronic arthritis patients treated with infliximab (IFX), (n = 81), etanercept (ETN) (n = 79), or adalimumab (ADA) (n = 79). Serum TNFi trough levels assessed at inclusion and every 4 months determined patients within/outside predefined therapeutic intervals, supporting change in prescription or drug switch. The primary endpoint was reduced drug prescription., Results: Compared to standard care, TDM reduced prescribed IFX [-12% (95% confidence interval -20, -3); p = 0.001] and ETN (-15% (-29, 1); p = 0.01], and prolonged the interdosing intervals of ETN [+235% (38, 432); p = 0.02] and ADA [+28% (6, 51); p = 0.04]. Time to drug switch was accelerated (χ2 = 6.03, p = 0.01). No group differences in adverse events, disease activity, or self-reported outcomes were shown, indicating equally sustained remission., Conclusions: TDM reduced prescription of IFX, ETN, and ADA and identified patients benefiting from accelerated drug switch, thereby minimizing treatment failure, risk of toxicity, and unnecessary adverse events.

Recently an individualisation algorithm has been developed and shown to significantly improve the diagnostic accuracy of creatine kinase (CK) and urea in endurance sports and Badminton. In this study, the applicability and benefit of this algorithm was evaluated using repeated measures data from 161 professional German soccer players monitored during the 2015-2017 seasons. Venous blood samples were collected after a day off (recovered state) and after a minimum of two strenuous training sessions within 48 h (non-recovered state) and analysed for CK and urea. Group-based reference ranges were derived from that same dataset to ensure the best possible reference for comparison. A z -test was conducted to analyse differences in error rates between individualised and group-based classifications. CK values for the individualised approach showed significantly lower error rates in the assessment of muscle recovery compared to both a population-based ( p  < .001; z -value: -17.01; test-pass error rate: 21 vs. 67%; test-fail: 19 vs. 64%) and a group-based cut-off ( p  < .001; z -value: -15.29; test-pass error rate: 65%; test-fail: 67%). It could be concluded that the assessment of muscle recovery in soccer using individualised interpretations of blood-borne markers may offer higher diagnostic accuracy than a population-based and a sample-specific group-based approach. Highlights Assessing muscle recovery via CK using individualised ranges seems to offer a higher diagnostic accuracy than a sample-specific group-based analysis.Using an individualised algorithm seems to be a promising approach to overcome diagnostic problems arising from large inter- and intraindividual variability in blood parameters as it significantly improved the diagnostic accuracy of CK as a recovery marker.As recovery assessment in elite soccer ultimately aims at the accurate detection of differences in the individual player this algorithm seems to offer coaches and sport scientists a more sensitive approach compared to group-specific evaluations.

Objective: Preliminary findings from selected health systems revealed interruptions in reproductive health care services due to the COVID-19 pandemic. We estimated changes in postpartum contraceptive provision associated with the start of the COVID-19 pandemic in Maine., Methods: We used the Maine Health Data Organization's All Payer Claims Database for deliveries from October 2015 through March 2021 (n = 45 916). Using an interrupted time-series analysis design, we estimated changes in provision rates of long-acting reversible contraception (LARC), permanent contraception, and moderately effective contraception within 3 and 60 days of delivery after the start of the COVID-19 pandemic. We performed 6- and 12-month analyses (April 2020-September 2020, April 2020-March 2021) as compared with the reference period (October 2015-March 2020). We used Poisson regression models to calculate level-change rate ratios (RRs) and 95% CIs., Results: The 6-month analysis found that provision of LARC (RR = 1.89; 95% CI, 1.76-2.02) and moderately effective contraception (RR = 1.51; 95% CI, 1.33-1.72) within 3 days of delivery increased at the start of the COVID-19 pandemic, while provision of LARC (RR = 0.95; 95% CI, 0.93-0.97) and moderately effective contraception (RR = 1.08; 95% CI, 1.05-1.11) within 60 days of delivery was stable. Rates of provision of permanent contraception within 3 days (RR = 0.70; 95% CI, 0.63-0.78) and 60 days (RR = 0.71; 95% CI, 0.63-0.80) decreased. RRs from the 12-month analysis were generally attenuated., Conclusion: Disruptions in postpartum provision of permanent contraception occurred at the beginning of the COVID-19 pandemic in Maine. Public health policies should include guidance for contraceptive provision during public health emergencies and consider designating permanent contraception as a nonelective procedure.

Objective: The aim of this study is to estimate the risk of a new mental health diagnosis within the first 24 months postpartum among women with common pregnancy conditions, overall and by rurality. Materials and Methods: This longitudinal population-based study used the Maine Health Data Organization's All-Payer Claims Data to estimate the cumulative risk of a new mental health disorder diagnosis in the first 24 months postpartum among women with deliveries during 2007-2019 and who did not have a mental health diagnosis before pregnancy. Cox models were used to estimate hazard ratios for common pregnancy conditions (prenatal depression, gestational diabetes [GDM], and hypertensive disorders of pregnancy [HDP]) on the new diagnosis of five mental health conditions, separately. Models were adjusted for maternal demographics and pregnancy characteristics. Results: Of the 123,125 deliveries, the cumulative risk of being diagnosed in the first 24 months postpartum with depression was 28%, anxiety 25%, bipolar disorder 3%, post-traumatic stress disorder 6%, and schizophrenia/psychotic disorder 1%. Women with prenatal depression were at higher risk of having a postpartum mental health diagnosis compared with women without prenatal depression (adjusted hazard ratios [aHRs] ranged from 2.5 [for anxiety] to 4.1 [for postpartum depression]). Risk of having postpartum depression was modestly higher among women with HDP, as was the risk of postpartum bipolar disorder among those with GDM. Findings were generally similar between women living in rural versus urban areas. Conclusions: Effective interventions to prevent, screen, and treat mental health conditions among women with pregnancy complications for an extended time postpartum are warranted.

Background: High mountainous environments are of particular interest as they play an essential role for life and human societies, while being environments which are highly vulnerable to climate change and land use intensification. Despite this, our knowledge of high mountain soils in South America and their microbial community structure is strikingly scarce, which is of more concern considering the large population that depends on the ecosystem services provided by these areas. Conversely, the Central Andes, located in the Mediterranean region of Chile, has long been studied for its singular flora, whose diversity and endemism has been attributed to the particular geological history and pronounced environmental gradients in short distances. Here, we explore soil properties and microbial community structure depending on drainage class in a well-preserved Andean valley on the lower alpine vegetation belt (~2500 m a.s.l.) at 33.5˚S. This presents an opportunity to determine changes in the overall bacterial community structure across different types of soils and their distinct layers in a soil depth profile of a highly heterogeneous environment., Methods: Five sites closely located (<1.5 km) and distributed in a well preserved Andean valley on the lower alpine vegetation belt (~2500 m a.s.l.) at 33.5˚S were selected based on a pedological approach taking into account soil types, drainage classes and horizons. We analyzed 113 soil samples using high-throughput sequencing of the 16S rRNA gene to describe bacterial abundance, taxonomic composition, and co-occurrence networks., Results: Almost 18,427 Amplicon Sequence Variant (ASVs) affiliated to 55 phyla were detected. The bacterial community structure within the same horizons were very similar validating the pedological sampling approach. Bray-Curtis dissimilarity analysis revealed that the structure of bacterial communities in superficial horizons (topsoil) differed from those found in deep horizons (subsoil) in a site-specific manner. However, an overall closer relationship was observed between topsoil as opposed to between subsoil microbial communities. Alpha diversity of soil bacterial communities was higher in topsoil, which also showed more bacterial members interacting and with higher average connectivity compared to subsoils. Finally, abundances of specific taxa could be considered as biological markers in the transition from topsoil to subsoil horizons, like Fibrobacterota, Proteobacteria, Bacteroidota for shallower soils and Chloroflexi, Latescibacterota and Nitrospirota for deeper soils., Conclusions: The results indicate the importance of the soil drainage conditions for the bacterial community composition, suggesting that information of both structure and their possible ecological relationships, might be useful in clarifying the location of the edge of the topsoil-subsoil transition in mountainous environments., (© 2023. The Author(s).)

Purpose: Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking., Patients and Methods: HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses., Results: HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay ( P trend < .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P < .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive ( P = .003) but not for HPV-negative patients ( P = .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020., Conclusion: Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.

The density of states (DOS) is fundamentally important for understanding physical processes in organic disordered semiconductors, yet hard to determine experimentally. We evaluated the DOS by considering recombination via tail states and using the temperature and open-circuit voltage (V&#95;{oc}) dependence of the ideality factor. By performing Suns-V&#95;{oc} measurements, we find that the energetic disorder increases deeper into the band gap, which is not expected for a Gaussian or exponential DOS. The linear dependence of the disorder on energy reveals the power-law DOS in organic solar cells.

Objectives: To estimate the association between rural residence and sequelae of hypertensive disorders of pregnancy (HDP) in the first year postpartum., Study Design: We used the Maine Health Data Organization's All Payer Claims Data to identify women with HDP who delivered during 2007-2019 and did not have chronic hypertension or pre-pregnancy cardiac conditions (n = 8882). We used Cox proportional hazards modeling to estimate rural-urban hazard ratios (HR) and 95% confidence intervals (CI), adjusting for HDP subtype, age, insurance, nulliparity, and co-morbidities. Results were stratified by HDP subtype and timing of acute care visits., Main Outcome Measures: Risk of at least one emergency room or inpatient visit related to hypertension or cardiovascular conditions in the first year postpartum and receipt of outpatient antihypertensive medications from 4 days to 1 year postpartum, separately., Results: Overall, risk of at least one acute care visit in the first year postpartum was not different between rural vs urban women (4.2% vs 4.2%; adjusted HR 0.98; 95% CI 0.79,1.21), and outpatient receipt of antihypertensive medication was not different (12.9% vs 12.8%; adjusted HR 0.99; 95% CI 0.87, 1.12). However, stratified analyses suggested some differences (e.g. preeclampsia with severe features: acute care visit adjusted HR 1.54; 95% CI 0.95, 2.49)., Conclusions: Rural and urban women do not differ in the risks of these common HDP sequelae, though rural women may have increased risk by HDP subtype or timing of acute care visit. Future research should investigate postpartum interventions for reducing HDP sequelae in rural and urban women., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KP has research contracts with AbbVie, GSK, and Sanofi that are unrelated to this study. The authors declare they have no other competing interests., (Copyright © 2023 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objectives: The present study aimed to assess the perception and change of mental and physical fatigue and to examine acute effects of mental recovery strategies in air rifle athletes across simulated competition days with two consecutive competition bouts., Design: We conducted a randomized counterbalanced crossover study., Method: 22 development air rifle athletes (M age  = 17.77 ± 4.0) of a regional squad participate in the study. The Short Recovery and Stress Scale (SRSS), perception of mental fatigue, physical fatigue, concentration and motivation as well as differential Ratings of Perceived Exertion (RPE) were used to assess recovery-stress states and fatigue states. During a recovery break, participants underwent two mental recovery strategies (powernap, systematic breathing) or a control condition. Total shooting scores were recorded for both competition bouts., Results: Study results revealed a significant increase of post ratings for mental ( p  < .001) and physical fatigue ( p  < .001) for both competition bouts. The correlation coefficient between change in mental and physical fatigue for both competitions revealed a shared variance of 7.9% and 18.6%, respectively. No significant group-based acute effects of the use of mental recovery strategies on shooting performance, and psychological and perceptual measures were found. On an individual level, results illustrated statistical relevant improvements of shooting performance after powernapping or systematic breathing., Conclusion: Mental and physical fatigue increased and accumulated across a simulated air rifle competition and mental fatigue emerged as a separate construct from physical fatigue. The use of strategies to accelerate mental recovery on an individual level (e.g., powernap, systematic breathing) may be a first step to manage a state of mental fatigue, but further studies on mental recovery strategies in an applied setting are needed., 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., (© 2023 Loch, Ferrauti, Meyer, Pfeiffer and Kellmann.)

Background Although depression is well established as an independent risk factor for cardiovascular disease (CVD) in the nonpregnant population, this association has largely not been investigated in pregnant populations. We aimed to estimate the cumulative risk of new CVD in the first 24 months postpartum among pregnant individuals diagnosed with prenatal depression compared with patients without depression diagnosed during pregnancy. Methods and Results Our longitudinal population-based study included pregnant individuals with deliveries during 2007 to 2019 in the Maine Health Data Organization's All Payer Claims Data. We excluded those with prepregnancy CVD, multifetal gestations, or no continuous health insurance during pregnancy. Prenatal depression and CVD (heart failure, ischemic heart disease, arrhythmia/cardiac arrest, cardiomyopathy, cerebrovascular disease, and chronic hypertension) were identified by International Classification of Diseases, Ninth Revision ( ICD-9 )/ International Classification of Diseases, Tenth Revision ( ICD-10 ) codes. Cox models were used to estimate hazard ratios (HRs), adjusting for potential confounding factors. Analyses were stratified by hypertensive disorder of pregnancy. A total of 119 422 pregnancies were examined. Pregnant individuals with prenatal depression had an increased risk of ischemic heart disease, arrhythmia/cardiac arrest, cardiomyopathy, and new hypertension (adjusted HR [aHR], 1.83 [95% CI, 1.20-2.80], aHR, 1.60 [95% CI, 1.10-2.31], aHR, 1.61 [95% CI, 1.15-2.24], and aHR, 1.32 [95% CI, 1.17-1.50], respectively). When the analyses were stratified by co-occurring hypertensive disorders of pregnancy, several of these associations persisted. Conclusions The cumulative risk of a new CVD diagnosis postpartum was elevated among individuals with prenatal depression and persists even in the absence of co-occurring hypertensive disorders of pregnancy. Further research to determine the causal pathway can inform postpartum CVD preventive measures.

Background and Aims: This study was designed to obtain daily weighed food intake of participants engaged in Alternate Day Feeding (ADF). Prior ADF studies have used self-reported food intake, a method that has received criticism for its limited accuracy., Subjects and Methods: Forty-nine university students received academic credit for participating in the study. Following a 10-day baseline period, participants underwent ADF for the next 8 days. Restricted daily intake to ∼ 75% of baseline food intake levels was followed by ad libitum intake on alternate days. Food intake was weighed before and after each meal. Daily body weight was also tracked., Intervention: After the baseline period, participants underwent 8 days of ADF during which they consumed ∼ 75% of baseline energy intake by weight followed by ad libitum intake on alternate days. The trial concluded with 2 additional days of ad libitum feeding, for a total study duration of 10 days., Results: Daily food intake was constant during the baseline period (slope = -0.93 g/d, p = 0.56), and did not differ significantly (995 g (95% CI [752, 1198]) from the total consumed on ad libitum ADF days (951 g (95% CI [777, 1227]). Intake on ad libitum days did not show a trend to increase during the intervention. Body weight declined significantly during ADF., Conclusions: ADF produces significant weight loss because food intake does not increase on ad libitum feeding days to compensate for reduced intake on restricted energy days. Data are consistent with prior work that suggests humans do not fully compensate for imposed deficits in energy intake., Competing Interests: Declaration of Competing Interest None of the authors have any financial or affiliation with any competing interest., (Copyright © 2023. Published by Elsevier Inc.)