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Despite the increasing demand for efficient and sustainable chemical processes, the development of scalable systems using biocatalysis for fine chemical production remains a significant challenge. We have developed a scalable flow system using immobilized enzymes to facilitate flavin-dependent biocatalysis, targeting as a proof-of-concept asymmetric alkene reduction. The system integrates a flavin-dependent Old Yellow Enzyme (OYE) and a soluble hydrogenase to enable H2-driven regeneration of the OYE cofactor FMNH2. Molecular hydrogen was produced by water electrolysis using a proton exchange membrane (PEM) electrolyzer and introduced into the flow system via a designed gas membrane addition module at a high diffusion rate. The flow system shows remarkable stability and reusability, consistently achieving >99% conversion of ketoisophorone to levodione. It also demonstrates versatility and selectivity in reducing various cyclic enones and can be extended to further flavin-based biocatalytic approaches and gas-dependent reactions. This electro-driven continuous flow system, therefore, has significant potential for advancing sustainable processes in fine chemical synthesis.

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Structural and chemical characterization of nanomaterials provides important information for understanding their functional properties. Nanomaterials with characteristic structure sizes in the nanometer range can be characterized by scanning transmission electron microscopy (STEM). In conventional STEM, two-dimensional (2D) projection images of the samples are acquired, information about the third dimension is lost. This drawback can be overcome by STEM tomography, where the three-dimensional (3D) structure is reconstructed from a series of projection images acquired using various projection directions. However, 3D measurements are expensive with respect to acquisition and evaluation time. Furthermore, the method is hardly applicable to beam-sensitive materials, i.e. samples that degrade under the electron beam. For this reason, it is desirable to know whether sufficient information on structural and chemical information can be extracted from 2D-projection measurements. In the present work, a comparison between 3D-reconstruction and 2D-projection characterization of structure and mixing in nanoparticle hetero-aggregates is provided. To this end, convolutional neural networks are trained in 2D and 3D to extract particle positions and material types from the simulated or experimental measurement. Results are used to evaluate structure, particle size distributions, hetero-aggregate compositions and mixing of particles quantitatively and to find an answer to the question, whether an expensive 3D characterization is required for this material system for future characterizations.

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Fermenting grape juice provides a habitat for a well-mapped and evolutionarily relevant microbial ecosystem consisting of many natural or inoculated strains of yeasts and bacteria. The molecular nature of many of the ecological interactions within this ecosystem remains poorly understood, with the partial exception of interactions of a metabolic nature such as competition for nutrients and production of toxic metabolites/peptides. Data suggest that physical contact between species plays a significant role in the phenotypic outcome of interspecies interactions. However, the molecular nature of the mechanisms regulating these phenotypes remains unknown. Here, we present a transcriptomic analysis of physical versus metabolic contact between two wine relevant yeast species, Saccharomyces cerevisiae and Lachancea thermotolerans. The data show that these species respond to the physical presence of the other species. In S. cerevisiae, physical contact results in the upregulation of genes involved in maintaining cell wall integrity, cell wall structural components, and genes involved in the production of H2S. In L. thermotolerans, HSP stress response genes were the most significantly upregulated gene family. Both yeasts downregulated genes belonging to the FLO family, some of which play prominent roles in cellular adhesion. qPCR analysis indicates that the expression of some of these genes is regulated in a species-specific manner, suggesting that yeasts adjust gene expression to specific biotic challenges or interspecies interactions. These findings provide fundamental insights into yeast interactions and evolutionary adaptations of these species to the wine ecosystem.IMPORTANCEWithin the wine ecosystem, yeasts are the most relevant contributors to alcoholic fermentation and wine organoleptic characteristics. While some studies have described yeast-yeast interactions during alcoholic fermentation, such interactions remain ill-defined, and little is understood regarding the molecular mechanisms behind many of the phenotypes observed when two or more species are co-cultured. In particular, no study has investigated transcriptional regulation in response to physical interspecies cell-cell contact, as opposed to the generally better understood/characterized metabolic interactions. These data are of direct relevance to our understanding of microbial ecological interactions in general while also creating opportunities to improve ecosystem-based biotechnological applications such as wine fermentation. Furthermore, the presence of competitor species has rarely been considered an evolutionary biotic selection pressure. In this context, the data reveal novel gene functions. This, and further such analysis, is likely to significantly enlarge the genome annotation space.

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BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

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PURPOSE: Intracranial hypertension (IH) frequently complicates cerebral venous thrombosis (CVT). Distinct neuroimaging findings are associated with IH, yet their discriminative power, reversibility and factors favoring normalization in prospective CVT patients are unknown. We determined test performance measures of neuroimaging signs in acute CVT patients, their longitudinal change under anticoagulation, association with IH at baseline and with recanalization at follow-up. METHODS: We included 26 consecutive acute CVT patients and 26 healthy controls. Patients were classified as having IH based on CSF pressure > 25 cmH2O and/or papilledema on ophthalmological examination or ocular MRI. We assessed optic nerve sheath diameter (ONSD), optic nerve tortuousity, bulbar flattening, lateral and IVth ventricle size, pituitary configuration at baseline and follow-up, and their association with IH and venous recanalization. RESULTS: 46% of CVT patients had IH. ONSD enlargement > 5.8 mm, optic nerve tortuousity and pituitary grade ≥ III had highest sensitivity, ocular bulb flattening and pituitary grade ≥ III highest specificity for IH. Only ONSD reliably discriminated IH at baseline. Recanalization was significantly associated with regressive ONSD and pituitary grade. Other neuroimaging signs tended to regress with recanalization. After treatment, 184.9 ± 44.7 days after diagnosis, bulbar flattening resolved, whereas compared with controls ONSD enlargement (p < 0.001) and partially empty sella (p = 0.017), among other indicators, persisted. CONCLUSION: ONSD and pituitary grading have a high diagnostic value in diagnosing and monitoring CVT-associated IH. Given their limited sensitivity during early CVT and potentially persistent alterations following IH, neuroimaging indicators can neither replace CSF pressure measurement in diagnosing IH, nor determine the duration of anticoagulation.

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The selective hydrogenation of acetylene catalyzed by Pd nanoparticles is industrially used to increase the purity of ethylene. Despite the implementation of Pd based catalysts on an industrial scale, little is known about metal-support interactions on a fundamental level due to the complexity of these systems. In this study, the influence of metal-support interactions between Pd nanoparticles and two electronically modified a-SiO2 thin films on acetylene hydrogenation is investigated under ultra-high vacuum (UHV) conditions. The hydrogenation is performed under isothermal reaction conditions using a pulsed molecular beam reactive scattering (pMBRS) technique. Besides the activity and selectivity of clean Pd particles also the impact of dehydrogenated species intentionally introduced a priori is elucidated, whereas the active phase of the catalyst is additionally characterized by CO infrared reflection-absorption spectroscopy (IRRAS) and post-mortem temperature-programmed reaction (TPR). Metal-support interactions are found to influence the catalytic properties of Pd particles by charge-transfer, where positive charging leads to increased activity for acetylene hydrogenation. However, the increased activity is accompanied by formation of undesired byproducts. The active sites for acetylene and ethylene hydrogenation are shown to be different as previously proposed by the A and E model. The availability of the two different active sites on the Pd nanoparticles is determined by dehydrogenated species, whose nature and stability can be tuned by metal-support interactions. Based on these findings an electronic model is proposed how selectivity for acetylene hydrogenation can be steered solely by metal-support interactions leading to blocking of unselective sites in situ.

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INTRODUCTION: Aphasia and neglect in combination with hemiparesis are reliable indicators of large anterior vessel occlusion (LAVO). Prehospital identification of these symptoms is generally considered difficult by emergency medical service (EMS) personnel. Therefore, we evaluated the simple non-paretic-hand-to-opposite-ear (NPE) test to identify aphasia and neglect with a single test. As the NPE test includes a test for arm paresis, we also evaluated the diagnostic ability of the NPE test to detect LAVO in patients with suspected stroke. METHODS: In this prospective observational study, we performed the NPE test in 1042 patients with suspected acute stroke between May 2021 and May 2022. We analyzed the correlation between the NPE test and the aphasia/neglect items of the National Institutes of Health Stroke Scale. Additionally, the predictive values of the NPE test for LAVO detection were calculated. RESULTS: The NPE test showed a strong, significant correlation with both aphasia and neglect. A positive NPE test result predicted LAVO with a sensitivity of 0.70, a specificity of 0.88, and an accuracy of 0.85. Logistic regression analysis showed an odds ratio of 16.14 (95% confidence interval 10.82-24.44) for predicting LAVO. CONCLUSION: The NPE test is a simple test for the detection of both aphasia and neglect. With its predictive values for LAVO detection being comparable to the results of LAVO scores in the prehospital setting, this simple test might be a promising test for prehospital LAVO detection by EMS personnel. Further prospective prehospital validation is needed.

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The use of tourniquets for life-threatening limb hemorrhage is standard of care in military and civilian medicine. The United States (U.S.) Department of Defense (DoD) Committee on Tactical Combat Casualty Care (CoTCCC) guidelines, as part of the Joint Trauma System, support the application of tourniquets within a structured system reliant on highly trained medics and expeditious evacuation. Current practices by entities such as the DoD and North Atlantic Treaty Organization (NATO) are supported by evidence collected in counter-insurgency operations and other conflicts in which transport times to care rarely went beyond one hour, and casualty rates and tactical situations rarely exceeded capabilities. Tourniquets cause complications when misused or utilized for prolonged durations, and in near-peer or peer-peer conflicts, contested airspace and the impact of high-attrition warfare may increase time to definitive care and limit training resources. We present a series of cases from the war in Ukraine that suggest tourniquet practices are contributing to complications such as limb amputation, overall morbidity and mortality, and increased burden on the medical system. We discuss factors that contribute to this phenomenon and propose interventions for use in current and future similar contexts, with the ultimate goal of reducing morbidity and mortality.

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Atomic electric fields in a thin GaN sample are measured with the centre-of-mass approach in 4D-scanning transmission electron microscopy (4D-STEM) using a 12-segmented STEM detector in a Spectra 300 microscope. The electric fields, charge density and potential are compared to simulations and an experimental measurement using a pixelated 4D-STEM detector. The segmented detector benefits from a high recording speed, which enables measurements at low radiation doses. However, there is measurement uncertainty due to the limited number of segments analysed in this study.

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BACKGROUND & AIMS: With the increase in patients at risk of advanced liver disease due to the obesity epidemic, there will be a need for simple screening tools for advanced liver fibrosis. Soluble suppression of tumorigenicity 2 (sST2) is a serum biomarker for fibrotic processes. The aim of this study was to evaluate sST2 as marker for liver fibrosis in patients successfully treated for chronic hepatitis C. METHODS: 424 patients from the Swiss Hepatitis C Cohort Study were screened for inclusion in this post-hoc cohort study. Inclusion criteria were sustained virological response (SVR), available elastography (VCTE) and serum samples for biomarker analysis before and after treatment. For the validation of sST2, values were compared to VCTE, FIB-4 and APRI using Spearman's correlation and AUROC analyses. RESULTS: Data of 164 subjects were finally analyzed. Median sST2 values slightly increased with VCTE-derived fibrosis stages and remained stable after reaching SVR within the respective fibrosis stage, suggesting that sST2 is not influenced by liver inflammation. However, correlation of sST2 pre- and post-treatment with VCTE was fair (Spearman's rho = 0.39 and rho = 0.36). The area under the curve (AUROC) for sST2 in detecting VCTE-defined F4 fibrosis (vs. F0-F3) before therapy was 0.74 (95%CI 0.65-0.83), and 0.67(95%CI 0.56-0.78) for the discrimination of F3/F4 fibrosis vs. F0-F2. Adding sST2 to either APRI or FIB-4, respectively, increased diagnostic performance of both tests. CONCLUSIONS: sST2 can potentially identify patients with advanced fibrosis as a single serum marker and in combination with APRI and FIB-4.

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PURPOSE: To quantify the effects of CSF pressure alterations on intracranial venous morphology and hemodynamics in idiopathic intracranial hypertension (IIH) and spontaneous intracranial hypotension (SIH) and assess reversibility when the underlying cause is resolved. METHODS: We prospectively examined venous volume, intracranial venous blood flow and velocity, including optic nerve sheath diameter (ONSD) as a noninvasive surrogate of CSF pressure changes in 11 patients with IIH, 11 age-matched and sex-matched healthy controls and 9 SIH patients, before and after neurosurgical closure of spinal dural leaks. We applied multiparametric MRI including 4D flow MRI, time-of-flight (TOF) and T2-weighted half-Fourier acquisition single-shot turbo-spin echo (HASTE). RESULTS: Sinus volume overlapped between groups at baseline but decreased after treatment of intracranial hypotension (p = 0.067) along with a significant increase of ONSD (p = 0.003). Blood flow in the middle and dorsal superior sagittal sinus was remarkably lower in patients with higher CSF pressure (i.e., IIH versus controls and SIH after CSF leak closure) but blood flow velocity was comparable cross-sectionally between groups and longitudinally in SIH. CONCLUSION: We were able to demonstrate the interaction of CSF pressure, venous volumetry, venous hemodynamics and ONSD using multiparametric brain MRI. Closure of CSF leaks in SIH patients resulted in symptoms suggestive of increased intracranial pressure and caused a subsequent decrease of intracranial venous volume and of blood flow within the superior sagittal sinus while ONSD increased. In contrast, blood flow parameters from 4D flow MRI did not discriminate IIH, SIH and controls as hemodynamics at baseline overlapped at most vessel cross-sections.

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A mechanochemical synthesis of sulfonimidamides by iron(II)-catalyzed exogenous ligand-free N-acyl nitrene transfer to sulfinamides is reported. The one-step method tolerates a wide range of sulfinamides with various substituents under solvent-free ambient conditions. Compared to its solution-phase counterpart, this mechanochemical approach shows better conversion and chemoselectivity. Mechanistic investigations by ESI-MS revealed the generation of crucial nitrene iron intermediates.

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If quantitative scanning transmission electron microscopy is used for very precise thickness measurements with atomic resolution, it is commonly referred to as ¼atom counting«. Due to scattering and the finite probe extent the signal recorded in one atomic column is dependent not only on its own height but also on the height of its neighbours. Especially for thicker specimens this crosstalk effect can have significant impact on the measured intensity. If it is not appropriately accounted for in the evaluation, it can result in a deterioration of accuracy that impedes the possibility of actual atom counting. However, as the number of possible neighbour configurations can be excessively large, a comprehensive consideration of all in the evaluation reference is neigh impossible. This work proposes a method that allows for the a-posteriori reduction of crosstalk during the evaluation by algebraic means. Based on a parametric model, which is described in detail in the article, the crosstalk is expressed by an invertible matrix. Applying the inverted matrix to the measurement yields crosstalk corrected intensity values with very little computational effort. These can subsequently be evaluated by direct comparison to simple reference data. The working principle of the method is presented on the example of crystalline gold. The crosstalk parametrisation is found by fitting a model to sets of specifically created multislice simulations. The parameters are given for both aberration corrected and uncorrected STEM. Subsequently the abilities and potential of the technique are assessed in simulative studies on multiple model systems including gold nanoparticles. Overall a significant and robust improvement of the attainable precision can be demonstrated making the proposed method a promising tool for reference-based atom counting.

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Conflicts between persons with opioid dependency and professionals in an acute hospital: A qualitative document analysis Abstract: Background: Opioid dependency is a chronic disease with severe health and social consequences. Patients often suffer from chronic infectious diseases, the consequences of which require treatment in an acute care hospital. On hospital wards, conflicts between patients with opioid dependency and professionals can be observed frequently. Aim: This study explores in which situations and for which reasons conflicts arise. Methods: Entries of professionals in patient charts were analysed qualitatively according to the Thematic Analysis. Results: Entries of 177 cases were analysed and three themes were identified. "Different priorities in the context of an acute hospital" showed that patients and professional teams often had divergent views on what is important during hospitalisation. "Self-medicating" provided evidence that patients suffered from symptoms that were inadequately treated and therefore self-medicated. The basic need "to be perceived as a human being" was not always met in the acute care hospital. Conclusions: Our results show causes and types of conflicts. Divergent values, under-treatment of addiction-specific symptoms and pain, and incomplete expertise among professionals appear to be causal, as does the lack of implementation of harm reduction.

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Strong Lewis acids are essential tools for manifold chemical procedures, but their scalable deployment is limited by their costs and safety concerns. We report a scalable, convenient, and inexpensive synthesis of stable diiminium-based reagents with a Lewis acidic carbon centre. Coordination with pyridine donors stabilises these centres; the 2,2'-bipyridine adduct shows a chelation effect at carbon. Due to high fluoride, hydride, and oxide affinities, the diiminium pyridine adducts are promising soft and hard Lewis acids. They effectively produce acylpyridinium salts from carboxylates that can acylate amines to give amides and imides even from electronically intractable coupling partners.

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Delirium incidence and phenotype differ between sexes. Sex differences in the selection of treatment strategies remain elusive. We evaluated sex-specific responses to non- and pharmacological management. In this observational prospective cohort study conducted at the University Hospital Zurich, Switzerland, 602 patients managed for delirium were analyzed. Remission and benefit ratios of treatments were calculated using Cox regression models. Baseline characteristics were similar in both sexes. Overall, 89% of all patients (540/602) received pharmacological management for delirium, most (77%) with one or two different medications. An equal number of male and female patients had either no medication ( P  = 0.321) or three and more medications ( P  = 0.797). Men had two different medications more often ( P  = 0.009), while women more frequently received one medication ( P  = 0.037). Remission rates within 20 days were higher in non-pharmacological treatment and similar between sexes, with odds of 1.36 in females, and 2.3 in males. Non-pharmacological treatment was equally efficacious in both sexes. Women who received supportive treatment and monotherapy had equal odds of remission. Men fared better with supportive care compared to pharmacologic therapies. Remission rates with different management strategies were similar between sexes. No sex differences were found regarding phenotypes, clinical course, and response to therapy.

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BACKGROUND & AIMS: Hepatitis A virus (HAV) infections are considered not to trigger innate immunity in vivo, in contrast to hepatitis C virus (HCV). This lack of induction has been imputed to strong interference by HAV proteases 3CD and 3ABC. We aimed to elucidate the mechanisms of immune activation and counteraction by HAV and HCV in vivo and in vitro. METHODS: Albumin-urokinase-type plasminogen activator/severe combined immunodeficiency (Alb/uPA-SCID) mice with humanised livers were infected with HAV and HCV. Hepatic cell culture models were used to assess HAV and HCV sensing by Toll-like receptor 3 and retinoic acid-inducible gene I/melanoma differentiation-associated protein 5 (RIG-I/MDA5), respectively. Cleavage of the adaptor proteins TIR-domain-containing adapter-inducing interferon-ß (TRIF) and mitochondrial antiviral-signalling protein (MAVS) was analysed by transient and stable expression of HAV and HCV proteases and virus infection. RESULTS: We detected similar levels of interferon-stimulated gene induction in hepatocytes of HAV- and HCV-infected mice with humanised liver. In cell culture, HAV induced interferon-stimulated genes exclusively upon MDA5 sensing and depended on LGP2 (laboratory of genetics and physiology 2). TRIF and MAVS were only partially cleaved by HAV 3ABC and 3CD, not sufficiently to abrogate signalling. In contrast, HCV NS3-4A efficiently degraded MAVS, as previously reported, whereas TRIF cleavage was not detected. CONCLUSIONS: HAV induces an innate immune response in hepatocytes via MDA5/LGP2, with limited control of both pathways by proteolytic cleavage. HCV activates Toll-like receptor 3 and lacks TRIF cleavage, suggesting that this pathway mainly contributes to HCV-induced antiviral responses in hepatocytes. Our results shed new light on the induction of innate immunity and counteraction by HAV and HCV. IMPACT AND IMPLICATIONS: Understanding the mechanisms that determine the differential outcomes of HAV and HCV infections is crucial for the development of effective therapies. Our study provides insights into the interplay between these viruses and the host innate immune response in vitro and in vivo, shedding light on previously controversial or only partially investigated aspects. This knowledge could tailor the development of new strategies to combat HCV persistence, as well as improve our understanding of the factors underlying successful HAV clearance.

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Geographic origin and terroir are very important parameters for wine and significantly impact price. Incorrect declarations are known to occur intentionally to increase profit, thus, measures for control are required. Accompanying paperwork has been shown to be unreliable, thus, control of the product itself is required. Here we investigate and compare the stable isotope pattern of South African (Western Cape Province) wine, and evaluate its potential for discrimination from Central European/Austrian wine. The results show that the isotope values of the investigated South African wine samples differ significantly from the values of average Austrian (Central European) wines. Thus, a differentiation of the products from these two regions by stable isotope analysis is generally straightforward. However, the data suggest that vintages from years with exceptionally hot and dry summer weather in Europe may reduce the differentiation between these regions. Therefore, this method is a potent tool for the discrimination of Austrian (Central European) and South African wines under current climatic conditions, although drier and hotter summer weather in Europe, which is likely to occur more frequently due to global climate change, may require further method adjustments in the future.

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Oxidative carbene organocatalysis, which proceeds via single electron transfer (SET) pathways, has been limited by the moderately reducing properties of deprotonated Breslow intermediates BI-s derived from thiazol-2-ylidene 1 and 1,2,4-triazolylidene 2. Using computational methods, we assess the redox potentials of BI-s based on ten different types of known stable carbenes and report our findings concerning the key parameters influencing the steps of the catalytic cycle. From the calculated values of the first oxidation potential of BI-s derived from carbenes 1 to 10, it appears that, apart from the diamidocarbene 7, all the others are more reducing than thiazol-2-ylidene 1 and the 1,2,4-triazolylidene 2. We observed that while the reducing power of BI-s significantly decreases with increasing solvent polarity, the redox potential of the oxidant can increase at a greater rate, thus facilitating the reaction. The cation, associated with the base, also plays an important role when a nonpolar solvent is used; large and weakly coordinating cations such as Cs+ are beneficial. The radical-radical coupling step is probably the most challenging step due to both electronic and steric constraints. Based on our results, we predict that mesoionic carbene 3 and abnormal NHC 4 are the most promising candidates for oxidative carbene organocatalysis.