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Percutaneous active mechanical circulatory support (MCS) devices are being increasingly used in the treatment of acute myocardial infarction-related cardiogenic shock (AMICS) despite conflicting evidence regarding their effect on mortality. We aimed to ascertain the effect of early routine active percutaneous MCS versus control treatment on 6-month all-cause mortality in patients with AMICS.

The dinuclear β-diketiminato complex [L1ClDy(μ-Cl)3DyL1(THF)] (1) (L1= {2,6-iPr2C6H3–NC(Me)CHC(Me)N-2,6-iPr2C6H3}−) was obtained by reaction of DyCl3with KL1in a molar ratio of 1:1 and used for the preparation of the mixed-ligand complex [L1Dy(μ-3,5-Cat)]2(2) by salt metathesis reaction with 3,5-CatK2(3,5-Cat −3,5-di-tert-butyl-catecholate). Reactions of 3,5-CatNa2with [L2LnCl2(THF)2] (Ln3+= Dy, Y) ligated with the less bulky ligand L2= {2,4,6-Me3C6H2–NC(Me)CHC(Me)N-2,4,6-Me3C6H2}−afforded the mixed-ligand THF-containing complexes [L2Ln(μ-3,5-Cat)(THF)]2(Ln3+= Dy (3a), Y (3b)). All new complexes were fully characterized, and the solid-state structures were determined by single-crystal X-ray diffraction. Magnetic measurements revealed single-molecule magnet behavior for the dysprosium complexes. Sub-Kelvin μSQUID studies confirm the SMM character of the systems, while CASSCF calculation along with simulation of the experimental data yields an antiferromagnetic interaction operating between the Dy3+ions.

The assessment and regulation of chemical toxicity to protect human health and the environment are done one chemical at a time and seldom at environmentally relevant concentrations. However, chemicals are found in the environment as mixtures, and their toxicity is largely unknown. Understanding the hazard posed by chemicals within the mixture is critical to enforce protective measures. Here, we demonstrate the application of bioactivity profiling of environmental water samples using the sentinel and ecotoxicology model species Daphniato reveal the biomolecular response induced by exposure to real-world mixtures. We exposed a Daphniastrain to 30 sampled waters of the Chaobai River and measured the gene expression response profiles. Using a multiblock correlation analysis, we establish correlations between chemical mixtures identified in 30 water samples with gene expression patterns induced by these chemical mixtures. We identified 80 metabolic pathways putatively activated by mixtures of inorganic ions, heavy metals, polycyclic aromatic hydrocarbons, industrial chemicals, and a set of biocides, pesticides, and pharmacologically active substances. Our data-driven approach discovered both known bioactivity signatures with previously described modes of action and new pathways linked to undiscovered potential hazards. This study demonstrates the feasibility of reducing the complexity of real-world mixture toxicity to characterize the biomolecular effects of a defined number of chemical components based on gene expression monitoring of the sentinel species Daphnia.

We investigated the plastic waste to ethylene (PtE) process through steam-oxygen gasification, methanation, and oxidative coupling of methane. Gasification was modeled using a stochastic reactor model, while the downstream process was modeled using Aspen Plus. The carbon efficiency of the process ranges from 13 to 23%, depending on feedstock used. We investigated a base case scenario with CO2venting and a case with CO2compression and transport. While 5.7 kgCO2eq/kg ethylene can be avoided in the former one, the latter one leads to an avoidance of 18.4 kgCO2eq/kg ethylene. The costs of CO2avoided are 666 €/tCO2eqand 230 €/tCO2eq, respectively.

Interleukin-23 inhibition is effective in treating ulcerative colitis. Guselkumab is a dual-acting, human IgG1, interleukin-23p19 subunit inhibitor that potently neutralises interleukin-23 and can bind to CD64. We aimed to evaluate the efficacy and safety of guselkumab as induction and maintenance therapy in patients with ulcerative colitis.

Viele Neuentwicklungen in der pädiatrischen Onkologie haben das Potenzial, die Überlebensraten weiter zu verbessern, Langzeitnebenwirkungen zu verringern und die Lebensqualität krebskranker Kinder und Jugendlicher zu erhöhen. Jüngste Fortschritte umfassen therapeutische Innovationen, technologische Fortschritte bei der Analyse von Tumorgewebe und Flüssigbiopsien sowie Verbesserungen in der ganzheitlichen Betreuung. Die genomische Identifizierung krebsspezifischer Mutationen und anderer molekularer Ziele ermöglicht eine gezielte Behandlung in personalisierten Therapieprotokollen, die die Ansprechraten verbessern und die Toxizität verringern. Analysen von Körperflüssigkeiten wie Blut, Knochenmark und Urin bieten neue nichtinvasive Methoden für Nachweis und Monitoring zirkulierender Tumorbiomarker und ermöglichen die Überwachung des Therapieansprechens und die frühe Diagnose von Rückfällen. Neuartige Immuntherapien wie CAR-T-Zell-Therapien und monoklonale Antikörper haben sich insbesondere bei akuten Leukämien und Neuroblastomen als erfolgreich erwiesen. Techniken wie die Protonentherapie haben die Präzision der Strahlentherapie verbessert und die Schädigung des umliegenden gesunden Gewebes minimiert. Dies ist vor allem bei pädiatrischen Patienten von entscheidender Bedeutung, bei denen die weitere Entwicklung des Kindes im Vordergrund steht. Umfassende psychosoziale Unterstützungsangebote stärken die Resilienz der Patienten und ihrer Familien. Die wachsende Zahl der Überlebenden einer pädiatrischen Krebserkrankung erfordert spezialisierte Nachsorgeangebote, denn die Überwachung von Spätfolgen wie sekundären Krebserkrankungen, kardiovaskulären Problemen und neurokognitiven Störungen ist entscheidend für die Verbesserung der langfristigen Ergebnisse.

Smart grids feature a bidirectional flow of electricity and data, enhancing flexibility, efficiency, and reliability in increasingly volatile energy grids. However, data from smart meters can reveal sensitive private information. Consequently, the adoption of smart meters is often restricted via legal means and hampered by limited user acceptance. Since metering data is beneficial for fault-free grid operation, power management, and resource allocation, applying privacy-preserving techniques to smart metering data is an important research problem. This work addresses this by using secure multi-party computation (SMPC), allowing multiple parties to jointly evaluate functions of their private inputs without revealing the latter. Concretely, we show how to perform power flow analysis on cryptographically hidden prosumer data. More precisely, we present a tailored solution to the power flow problem building on an SMPC implementation of Newton’s method. We analyze the security of our approach in the universal composability framework and provide benchmarks for various grid types, threat models, and solvers. Our results indicate that secure multi-party computation can be able to alleviate privacy issues in smart grids in certain applications.

IMPORTANCE: Mechanical circulatory support with a microaxial flow pump (MAFP) has been shown to improve survival in ST-elevation myocardial infarction–induced cardiogenic shock (STEMI-CS). Understanding the impact on hemodynamic stability over time is crucial for optimizing patient treatment. OBJECTIVE: To determine if an MAFP reduces the need for pharmacological circulatory support without compromising hemodynamics compared with standard care in STEMI-CS. DESIGN, SETTING, AND PARTICIPANTS: This was a substudy of the Danish-German (DanGer) Shock trial, an international, multicenter, open-label randomized clinical trial. Patients from 14 heart centers across Denmark, Germany, and the UK were enrolled. Inclusion criteria for the trial were STEMI and systolic blood pressure less than 100 mm Hg or ongoing vasopressor treatment, left ventricular ejection fraction less than 45%, and arterial lactate level greater than 2.5 mmol/L. Of the enrolled patients, after exclusions from death in the catheterization laboratory or immediately on intensive care unit (ICU) admission, the remaining patients had serial recordings of hemodynamics, arterial lactate, and use of vasoactive drugs. Patients who were in comas after cardiac arrest and patients with mechanical complications or right ventricular failure were excluded. Data were analyzed from May to September 2024. INTERVENTIONS: MAFP and standard of care or standard of care alone. MAIN OUTCOMES AND MEASURES: Hemodynamic status in terms of heart rate and blood pressure, metabolic status in terms of arterial lactate concentration, and vasoactive-inotropic score (VIS). The clinical events during the first 72 hours were as follows: death from all causes, escalation of mechanical circulatory support, and discharge alive from the ICU. RESULTS: From 355 enrolled patients, 324 (mean [IQR] age, 68 [58-75] years; 259 male [80%]) underwent ICU treatment (169 [52%] in the MAFP group, 155 [48%] in the standard-care group). Baseline characteristics were balanced. There was no difference in heart rate between groups, and mean arterial pressure was above the treatment target of 65 mm Hg in both groups but was achieved with a lower VIS in the MAFP group. No difference in arterial lactate level was found between groups at randomization, but on arrival to the ICU, the MAFP group had significantly lower arterial lactate levels compared with the standard-care group (mean difference, 1.3 mmol/L; 95% CI, 0.7-1.9 mmol/L), a difference that persisted throughout the first 24 hours of observation. The MAFP group achieved lactate normalization (<2 mmol/L) 12 hours (95% CI, 5-18 hours) before the standard-care group. CONCLUSIONS AND RELEVANCE: Use of a MAFP reduces the use of vasopressors and inotropic medication while maintaining hemodynamic stability and achieving faster normalization of lactate level in patients with STEMI-CS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01633502

BackgroundDelayed cerebral ischemia (DCI) is one of the main contributors to poor clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). Endovascular spasmolysis with intra-arterial nimodipine (IAN) may resolve angiographic vasospasm, but its effect on infarct prevention and clinical outcome is still unclear. We report the effect of IAN on infarction rates and functional outcome in a consecutive series of SAH patients.MethodsTo assess the effectiveness of IAN, we collected functional outcome data of all SAH patients referred to a single tertiary center since its availability (2011–2020). IAN was primarily reserved as a last tier option for DCI refractory to induced hypertension (iHTN). Functional outcome was assessed after 12 months according to the Glasgow Outcome Scale (GOS, favorable outcome = GOS4-5).ResultsOut of 376 consecutive SAH patients, 186 (49.5%) developed DCI. Thereof, a total of 96 (25.5%) patients remained unresponsive to iHTN and received IAN. DCI-related infarction was observed in 44 (45.8%) of IAN-treated patients with a median infarct volume of 111.6 mL (Q1: 51.6 to Q3: 245.7). Clinical outcome was available for 84 IAN-treated patients. Of those, a total of 40 (47.6%) patients reached a favorable outcome after 1 year. Interventional complications were observed in 9 (9.4%) of the IAN-treated patients.ConclusionIntra-arterial spasmolysis using nimodipine infusion was associated with low treatment specific complications. Despite presenting a subgroup of severely affected SAH patients, almost half of IAN-treated patients were able to lead an independent life after 1 year of follow-up.Trial registration numberGerman Clinical Trial Register DRKS00030505.

ABSTRACTAlthough strategic entrepreneurship (SE) and strategic human capital are both crucial for competitive advantage, there is limited knowledge of how SE affects human capital levels within a firm. This study examines the relationship between SE and both employee recruitment and employee retention by drawing on an integrated framework of strategic human capital and incorporating a uniquely created direct construct for measuring SE’s complete domain. Results from survey data of 576 UK-based small- and medium-sized firms indicate that SE is positively related to both employee retention and recruitment. We document the moderating effects of corporate reputation and competitive intensity on those relations.

The comparative benefits and harms of available interventions for ADHD in adults remain unclear. We aimed to address these important knowledge gaps.

The increasing need for larger bandwidth to support faster transfer rates in modern telecommunication systems, like the introduction of the 5G cellular standard in 2019 and the ongoing research into 6G, is resulting in a worldwide increase in power consumption [1]. Power amplifiers (PAs) in base stations are the main contributors to this power consumption [2]. Besides their power-added efficiency, the gain and the linearity of these amplifiers are important because in modern wideband (WB) systems, no power can be leaked into adjacent channels. The challenges become even greater with the use of spectral-efficient modulation schemes that produce signals with large amplitude variations [3]. Therefore, WB-modulated measurements play a critical role in evaluating the performance of RF systems. Unlike narrow-band techniques, which may overlook the nonlinear distortion effects inherent in modern communication systems, WB measurements provide a more comprehensive understanding across a broader frequency spectrum. In today’s communication landscape, where high-speed data transmission and sophisticated modulation techniques are prevalent, the need for WB-modulated measurements is more significant than ever. These measurements allow engineers to accurately assess the impact of nonlinear distortion on signal quality and integrity, ensuring reliable operation in demanding applications. Engineers can also identify and mitigate issues such as spectral regrowth, phase noise, and amplitude drop, which can degrade system performance and compromise the user’s experience. Additionally, these measurements can be employed to optimize system designs, enhance signal quality, and minimize the risk of interference and signal degradation in real-world environments.

Heat treatment is an essential step in achieving the desired characteristics in steels. Quenched and tempered (Q&T) steels are often tempered to adjust the strength-ductility ratio by taking advantage of the precipitation of carbides. In practice, many parts already contain residual stresses, for example due to the temperature gradients during surface hardening, and therefore tempering takes place under the influence of these stresses. The occurring transformation induced plasticity (TRIP) means significant plastic deformation during a phase transformation under a stress below the material’s yield strength. In this work, tempering TRIP of three different Q&T steels has been studied by means of dilatometry, hardness measurements, and scanning electron microscopy. The heating rate, as well as the direction and level of applied stress, have been varied. The results have proven the existence of TRIP strain during continuous tempering and its linear dependence on the fraction of the precipitates. A higher amount of carbon results in a growth of the precipitates surface area percentage, leading to an increase in the TRIP strain and consequently the TRIP constant. This indicates the presence of the Greenwood–Johnson effect, which relates TRIP to the difference in volume between the existing and forming phases.

Capsules are long-chain carbohydrate polymers that envelop the surfaces of many bacteria, protecting them from host immune responses. Capsule biosynthesis enzymes are potential drug targets and valuable biotechnological tools for generating vaccine antigens. Despite their importance, it remains unknown how structurally variable capsule polymers of Gram-negative pathogens are linked to the conserved glycolipid anchoring these virulence factors to the bacterial membrane. Using Actinobacillus pleuropneumoniaeas an example, we demonstrate that CpsA and CpsC generate a poly(glycerol-3-phosphate) linker to connect the glycolipid with capsules containing poly(galactosylglycerol-phosphate) backbones. We reconstruct the entire capsule biosynthesis pathway in A. pleuropneumoniaeserotypes 3 and 7, solve the X-ray crystal structure of the capsule polymerase CpsD, identify its tetratricopeptide repeat domain as essential for elongating poly(glycerol-3-phosphate) and show that CpsA and CpsC stimulate CpsD to produce longer polymers. We identify the CpsA and CpsC product as a wall teichoic acid homolog, demonstrating similarity between the biosynthesis of Gram-positive wall teichoic acid and Gram-negative capsules.

Objective: South Asians represent the largest non-white ethnic group in Canada and were disproportionately impacted by the COVID-19 pandemic. We sought to determine the factors associated with vaccine hesitancy in South Asian Canadians. Methods: We conducted a cross-sectional analysis of vaccine hesitancy using data collected at the baseline assessment of a prospective cohort study, COVID CommUNITY South Asian. Participants (18 + years) were recruited from the Greater Toronto and Hamilton Area in Ontario (ON) and the Greater Vancouver Area in British Columbia (BC) between April and November 2021. Demographic characteristics and vaccine attitudes measured by the Vaccine Attitudes Examination (VAX) scale were collected. Each item is scored on a 6-point Likert scale, and higher scores reflect greater hesitancy. A multivariable linear mixed effects model was used to identify sociodemographic factors associated with vaccine hesitancy, adjusting for multiple covariates. Results: A total of 1496 self-identified South Asians (52% female) were analyzed (mean age = 38.5 years; standard deviation (SD): 15.3). The mean VAX score was 3.2, SD: 0.8 [range: 1.0‒6.0]. Factors associated with vaccine hesitancy included: time since immigration (p = 0.04), previous COVID-19 infection (p < 0.001), marital status (p < 0.001), living in a multigenerational household (p = 0.03), age (p = 0.02), education (p < 0.001), and employment status (p = 0.001). Conclusion: Among South Asians living in ON and BC, time since immigration, prior COVID-19 infection, marital status, living in a multigenerational household, age, education, and employment status were associated with vaccine hesitancy. This information can be used to address vaccine hesitancy in the South Asian population in future COVID-19 waves or pandemics.

Accurate reservoir modeling during the field development phase is a principal factor in defining between poor and excellent economic performance of an asset. However, traditional methods of analysis constrain any [...]

We study the role of bargaining power and outside options with respect to the pricing of over-the-counter interbank loans using a bilateral Nash bargaining model, and we test the model predictions with detailed transaction-level data from the euro-area interbank market. We find that lender banks with greater bargaining power over their borrowers charge higher interest rates, whereas the lack of alternative investment opportunities for lenders lowers bilateral interest rates. Moreover, we find that when lenders that are not eligible to earn interest on excess reserves (IOER) lend funds to borrowers with access to the IOER facility, they do so at rates that are below the IOER rate; in turn, these borrowers put the funds in their reserve accounts to earn the spread. Our findings highlight that this persistent arbitrage crucially depends on lenders' limited bilateral bargaining power. We examine implications of these findings for the transmission of euro-area monetary policy. KEYWORDS bargaining power, monetary policy, money market segmentation, over-the-counter market JEL CLASSIFICATION E4,E58,G21, 1 | INTRODUCTION In most financial systems, only selected financial institutions (banks hereafter) can hold and trade central bank reserves. The interest rate that banks charge to borrowers of these [...]

Sleep is integral to cardiovascular health1,2. Yet, the circuits that connect cardiovascular pathology and sleep are incompletely understood. It remains unclear whether cardiac injury influences sleep and whether sleep-mediated neural outputs contribute to heart healing and inflammation. Here we report that in humans and mice, monocytes are actively recruited to the brain after myocardial infarction (MI) to augment sleep, which suppresses sympathetic outflow to the heart, limiting inflammation and promoting healing. After MI, microglia rapidly recruit circulating monocytes to the brain’s thalamic lateral posterior nucleus (LPN) via the choroid plexus, where they are reprogrammed to generate tumour necrosis factor (TNF). In the thalamic LPN, monocytic TNF engages Tnfrsf1a-expressing glutamatergic neurons to increase slow wave sleep pressure and abundance. Disrupting sleep after MI worsens cardiac function, decreases heart rate variability and causes spontaneous ventricular tachycardia. After MI, disrupting or curtailing sleep by manipulating glutamatergic TNF signalling in the thalamic LPN increases cardiac sympathetic input which signals through the β2-adrenergic receptor of macrophages to promote a chemotactic signature that increases monocyte influx. Poor sleep in the weeks following acute coronary syndrome increases susceptibility to secondary cardiovascular events and reduces the heart’s functional recovery. In parallel, insufficient sleep in humans reprogrammes β2-adrenergic receptor-expressing monocytes towards a chemotactic phenotype, enhancing their migratory capacity. Collectively, our data uncover cardiogenic regulation of sleep after heart injury, which restricts cardiac sympathetic input, limiting inflammation and damage.

ABSTRACTBackgroundTargeting the enzyme L-Arginine:glycine amidinotransferase (AGAT) to reduce the formation of guanidinoacetate (GAA) in patients with guanidinoacetate methyltransferase (GAMT) deficiency, we attempted to identify drugs for repurposing that reduce the expression of AGAT via transcriptional inhibition.Research Design and MethodsThe authors applied a HeLa cell line stably expressing AGAT promoter and firefly luciferase reporter for high-content screening and secondary screening. For further assessment, the authors integrated Nanoluc luciferase as a reporter into the endogenous AGAT gene in HAP1 cell lines and used the human immortalized cell line RH30 as model of GAMT deficiency.ResultsScreening 6,000 drugs and drug-like compounds, the authors identified 43 and 34 high-score candidates as inhibitors and inducers of AGAT promoter-reporter expression, respectively. After further deselection considering dose response, drug toxicity, topical formulations, price, and accessibility, the authors assessed seven candidates and found none of them demonstrating efficacy in HAP1 and RH30 cells and warranting further assessment.ConclusionThe selection of the test models is crucial for screening of gene repressor drugs. Almost all drugs with an impact on gene expression had off-target effects. It is unlikely to find drugs that are selective inhibitors of AGAT expression, rendering pharmacological AGAT gene repression a risky approach for the treatment of GAMT deficiency.

The concept of metabolic health, particularly in obesity, has attracted a lot of attention in the scientific community, and is being increasingly used to determine the risk of cardiovascular diseases and diabetes mellitus-related complications. This Review assesses the current understanding of metabolically healthy obesity (MHO). First, we present the historical evolution of the concept. Second, we discuss the evidence for and against its existence, the usage of different definitions of MHO over the years and the efforts made to provide novel definitions of MHO. Third, we highlight epidemiological data with regard to cardiovascular risk in MHO, which is estimated to be moderately elevated using widely used definitions of MHO when compared with individuals with metabolically healthy normal weight, but potentially not elevated using a novel definition of MHO. Fourth, we discuss novel findings about the physiological mechanisms involved in MHO and how such knowledge helps to identify and characterize both people with MHO and those with metabolically unhealthy normal weight. Finally, we address how the concept of MHO can be used for risk stratification and treatment in clinical practice.

Fully textured perovskite silicon tandem solar cells are promising for future low-cost photovoltaic deployment. However, the fill factor and open-circuit voltage of these devices are currently limited by the high density of defects at grain boundaries and at interfaces with charge transport layers. To address this, we devise a strategy to simultaneously enhance perovskite crystallization and passivate the perovskite/C60interface. By incorporating urea (CO(NH2)2) as an additive in the solution step of the hybrid evaporation/spin-coating perovskite deposition method, the crystallization kinetics are accelerated, leading to the formation of the desired photoactive phase at room temperature. With that, perovskite films with large grain sizes (>1 μm) and improved optoelectronic quality are formed at low annealing temperatures (100°C). Concurrently, remnant urea molecules are expelled at the perovskite surface, which locally displaces the C60layer, thus reducing interfacial non-radiative recombination losses. With this strategy, the resulting tandem solar cells achieve 30.0% power conversion efficiency.

Nontargeted screening (NTS) utilizing liquid chromatography electrospray ionization high-resolution mass spectrometry (LC/ESI/HRMS) is increasingly used to identify environmental contaminants. Major differences in the ionization efficiency of compounds in ESI/HRMS result in widely varying responses and complicate quantitative analysis. Despite an increasing number of methods for quantification without authentic standards in NTS, the approaches are evaluated on limited and diverse data sets with varying chemical coverage collected on different instruments, complicating an unbiased comparison. In this interlaboratory comparison, organized by the NORMAN Network, we evaluated the accuracy and performance variability of five quantification approaches across 41 NTS methods from 37 laboratories. Three approaches are based on surrogate standard quantification (parent-transformation product, structurally similar or close eluting) and two on predicted ionization efficiencies (RandFor-IEand MLR-IE). Shortly, HPLC grade water, tap water, and surface water spiked with 45 compounds at 2 concentration levels were analyzed together with 41 calibrants at 6 known concentrations by the laboratories using in-house NTS workflows. The accuracy of the approaches was evaluated by comparing the estimated and spiked concentrations across quantification approaches, instrumentation, and laboratories. The RandFor-IEapproach performed best with a reported mean prediction error of 15× and over 83% of compounds quantified within 10× error. Despite different instrumentation and workflows, the performance was stable across laboratories and did not depend on the complexity of water matrices.

Word problem-solving is one major area in mathematics that has been identified as being particularly challenging for students, specifically for those with learning disabilities (LDs) and emotional and behavioral disorders (EBD). This study aims at evaluating the effects of a strategic math intervention with concept maps on the ability to solve word problems (addition and subtraction problems, number range of thousand) among students with LDs and EBD from the eighth grade. A multiple-baseline design across participants (N = 9) was applied to evaluate the intervention, which was held three times a week over a 6-week period. Overall, the results demonstrated a functional relation between the amount of correctly solved word problem tasks and the intervention. All nine students improved in word problem-solving, as evidenced by the fact that more tasks were solved, with a higher score in the intervention phase compared with the baseline (between-case standardized mean difference was 1.84; 95% confidence interval [1.24, 2.44]). The social validity data display that all students found the intervention helpful but also partly exhausting. The limitations and implications of this study are discussed.

Mittelständische Unternehmen stehen unter einem enormen Marktdruck. Sie bewegen sich im Spannungsfeld von steigenden Kundenanforderungen, eines zunehmenden Fachkräftemangels sowie komplexer gesetzlicher Rahmenbedingungen u. a. in Bezug auf Cybersecurity, Nachhaltigkeit sowie Sorgfaltspflichten bezüglich Menschenrechte und Klimaschutz. Digitalisierung und Automatisierung von Geschäftsprozessen verspricht, diesen Druck auf die Unternehmen zu reduzieren, den Anforderungen verschiedener Stakeholder in kürzerer Zeit nachzukommen und Freiheit für strategische Handlungsfähigkeit zu gewinnen.

Current cardiometabolic disease prevention guidelines recommend increasing dietary unsaturated fat intake while reducing saturated fats. Here we use lipidomics data from a randomized controlled dietary intervention trial to construct a multilipid score (MLS), summarizing the effects of replacing saturated fat with unsaturated fat on 45 lipid metabolite concentrations. In the EPIC-Potsdam cohort, a difference in the MLS, reflecting better dietary fat quality, was associated with a significant reduction in the incidence of cardiovascular disease (−32%; 95% confidence interval (95% CI): −21% to −42%) and type 2 diabetes (−26%; 95% CI: −15% to −35%). We built a closely correlated simplified score, reduced MLS (rMLS), and observed that beneficial rMLS changes, suggesting improved dietary fat quality over 10 years, were associated with lower diabetes risk (odds ratio per standard deviation of 0.76; 95% CI: 0.59 to 0.98) in the Nurses’ Health Study. Furthermore, in the PREDIMED trial, an olive oil-rich Mediterranean diet intervention primarily reduced diabetes incidence among participants with unfavorable preintervention rMLS levels, suggestive of disturbed lipid metabolism before intervention. Our findings indicate that the effects of dietary fat quality on the lipidome can contribute to a more precise understanding and possible prediction of the health outcomes of specific dietary fat modifications.

High-strength and stiffness materials can further increase the lightweight construction potential of additive manufacturing. One way to achieve this, is to produce particle-reinforced aluminum matrix composites (PAMCs). A significant increase in strength can be achieved with ceramic particles smaller than 6 μm and a volume fraction of 20 to 30 % in other metallurgical processes. Due to the larger interparticle forces compared to the gravitational force, such powder mixtures are not flowable and cannot be recoated in PBF-LB with static recoaters like rubber lips and metal blades. Two approaches were compared to solve this problem. Firstly, the new broadband ultrasonic excitation of the recoater metal combs and secondly, flow enhancing with nanoparticles. The influence of the approaches was investigated by image analysis of the recoated layers for defects in an SLM 280 HL 1.0. Broadband vibration enables reliable recoating of AlSi10Mg powders mixed with up to 20 vol% 6 μm boron carbide particles without layer defects. Combined with TiC nanoparticle coating, 25 vol% are possible. The solution can securely be operated in build jobs.

Alkanolamine-based chemical absorption carbon capture may present a promising pathway to achieving much-needed CO2emissions reductions, although high energy requirements pose a key challenge. A potential solution could be to replace water, the traditional alkanolamine cosolvent, with an organic (nonaqueous) alternative. To this end, this work presents the final step in parametrizing the s-SAFT-γ Mie predictive group-contribution equation of state (EoS) for alkanolamine/CO2/organic cosolvent systems. s-SAFT-γ Mie is extended to CO2/glyme and CO2/ethylene glycol mixtures and finally to alkanolamine/CO2/organic cosolvent systems. Using only a single parameter set, s-SAFT-γ Mie provides qualitatively meaningful predictions for a wide range of systems. This highlights the broad generalizability afforded by the group-contribution approach. While this generalizability comes at the cost of quantitative accuracy for individual systems, s-SAFT-γ Mie’s robust predictive capabilities and wide applicability render it suitable for potential use within an alkanolamine solvent/organic cosolvent screening tool.

The need for sustainability is driving the transition from linear to circular production. Customers, driven by the desire for innovation, prefer new products with the latest cutting-edge functions and design. The problem is that used products from older product generations are hence less attractive, leading to a limited market for remanufactured products and generating less revenue than their new counterparts. Therefore, this research addresses the problem of reprocessing and technologically updating used products into the newest product generation. To address this problem of reprocessing and technological updating with a Circular Factory, the product’s function fulfillment must be predicted in different situations in a Circular Factory. Three key challenges in which the function fulfillment must be predicted are identified as: Analysis and Diagnostics of Used Products and Subsystems, Prediction for Pairing and Reprocess of the Embodimentand Design for Circular Factory. A model-based approach is presented to address these three key challenges by predicting product function fulfillment to enable cross-generational use of subsystems and components. Five different types of models are proposed: A Functional Model, a Reliability Modeland a Reference Architecture Modelat the high level of general product modeling, as well as a Digital Twinof an object instance and a Tolerance Schemeat the level of individual instances. A theoretical case study shows the possible application in a Circular Factory using the example of an angle grinder. However, it’s essential to acknowledge that substantial work is needed for the enhancement or development of these models before practical application. Successful application of these models allows the Circular Factory not only to maintain but also to increase the value of reprocessed products to enable offering on the primary market and contribute to the vision of realizing a perpetual innovative product.

The integration of both linear and circular processes in one production system poses significant challenges. In particular, the reprocessing of end-of-life products is associated with uncertainties at all levels of the production system, from the initial planning and control through to the executing production hardware and intralogistics. To address these challenges, this article presents approaches for self-learning and autonomously adapting production equipment for the Circular Factory. Initially, hardware and software solutions are developed to cover the necessary processes. Reprocessing is covered by modular and reconfigurable manufacturing cells, which also include new process chains such as the combination of additive-subtractive processes. The provided capabilities must be applied to ever new products, for example by transferring human procedures for unknown products to the production equipment. Lastly, an overall robust and dynamic production planning and control system is developed that maintains continuous operation even in unforeseen situations. The resulting highly dynamic overall system is connected by an autonomous intralogistics system.

The article discusses the legacy of Joseph Haydn and his significant contributions to the development of the keyboard sonata. Topics include Haydn's embrace of the galant style and its emphasis on pleasing and witty music, the incorporation of humor and musical pranks in his compositions, and the technical accessibility of his piano sonatas, making them suitable for late-intermediate or early-advanced students.

IMPORTANCE: Outcomes for patients with unresectable stage III non–small cell lung cancer (NSCLC) treated with chemoradiation therapy (CRT) have improved with adjuvant immune checkpoint inhibitors, with a reported 5-year overall survival benefit of approximately 10% for adjuvant durvalumab vs placebo after completion of CRT without progression and with preserved performance status. Starting atezolizumab prior to CRT may allow more patients to benefit from immunotherapy. OBJECTIVE: To evaluate clinical outcomes of patients treated with atezolizumab before and after CRT for unresectable stage III NSCLC. DESIGN, SETTING, AND PARTICIPANTS: This single-cohort, phase II, nonrandomized controlled trial was conducted at 11 US sites. Patients with pathologically confirmed, unresectable stage III NSCLC who were treatment naive and had good performance status were enrolled between January 3, 2018, and July 24, 2019. Data were locked on March 21, 2023. INTERVENTIONS: Patients received four 21-day cycles of atezolizumab, 1200 mg intravenously, with therapy administered on day 1 of each cycle. Patients not experiencing tumor progression continued to CRT (60 Gy to involved fields) concurrent with weekly carboplatin area under the curve of 2 and paclitaxel, 50 mg/m2, followed by planned consolidation carboplatin area under the curve of 6 and paclitaxel, 200 mg/m2, for two 21-day cycles. Patients not experiencing progression continued atezolizumab, 1200 mg, every 21 days to complete 1 year of therapy. MAIN OUTCOMES AND MEASURES: The primary end point was the disease control rate at 12 weeks. Secondary end points were progression-free survival, overall survival, overall response rate, safety, and translational science end points. RESULTS: A total of 62 patients (median [range] age, 63.9 [38.1-86.5] years; 32 female [51.6%]) were enrolled and received at least 1 dose of atezolizumab. The disease control rate at 12 weeks was 74.2% (80% CI, 65.7%-81.4%). Median progression-free survival was 30.0 months (95% CI, 15.8 to not evaluable), and the median overall survival was not reached. The overall survival rate at 24 months was 73.7% (95% CI, 63.4%-85.7%), and the overall response rate was 66.2%. Seventeen patients (27.4%) experienced grade 3 or higher immune-related adverse events, including 1 with grade 5 pneumonitis and 1 with grade 4 Guillain-Barré syndrome. Thirty patients (48.4%) experienced grade 3 or higher treatment-related adverse events. CONCLUSIONS AND RELEVANCE: These findings suggest that neoadjuvant atezolizumab merits further study based on safety and encouraging outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03102242

IMPORTANCE: Whether patients with Child-Pugh class B (CP-B) cancer with unresectable hepatocellular carcinoma (uHCC) benefit from active anticancer treatment vs best supportive care (BSC) is debated. OBJECTIVE: To evaluate the association of immune checkpoint inhibitor (ICI)–based therapies vs BSC with overall survival (OS) of patients with uHCC and CP-B liver dysfunction. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, multicenter, international clinical case series examined data of patients with CP-B with uHCC who were receiving first-line ICI-based regimens from September 2017 to December 2022 whose data were extracted from an international consortium and compared with a cohort of patients with CP-B receiving BSC. Patients were treated in tertiary care centers across Europe, US, and Asia in routine clinical practice. After applying the inclusion criteria, 187 and 156 patients were left in the ICI and BSC groups, respectively. The propensity score was calculated for the following variables: age, alpha-fetoprotein levels, Child-Pugh score, extrahepatic spread, portal vein tumor thrombosis, cirrhosis, ascites, and baseline Eastern Cooperative Oncology Group performance status. EXPOSURES: Patients in the ICI group received first-line systemic therapy with either atezolizumab plus bevacizumab (A+B) (n = 141) or nivolumab (n = 46). MAIN OUTCOMES AND MEASURES: OS in the inverse probability of treatment weighting (IPTW) populations was the main outcome, and it was estimated with Kaplan-Meier method; univariable Cox regression test was used to make comparisons between the 2 groups. RESULTS: The median age was 66 (IQR, 61-72) and 73 (IQR, 66-81) years in the ICI (33 women [18%]) and BSC groups (41 women [26%]), respectively. In the IPTW populations, median OS was significantly longer in the ICI group (7.50 months; 95% CI, 5.62-11.15) compared with BSC (4.04 months; 95% CI, 3.03-5.03; hazard ratio, 0.59; 95% CI, 0.43-0.80; P < .001). Multivariable analysis confirmed that ICI exposure was associated with a reduction of approximately 50% in the risk of death (hazard ratio, 0.55; 95% CI, 0.35-0.86; P < .001), and the presence of portal vein tumor thrombosis, an Eastern Cooperative Oncology Group performance score of greater than 1, and alpha-fetoprotein levels of 400 ng/mL or greater were associated with increased risk of death. CONCLUSIONS AND RELEVANCE: The results of this case series provide comparative evidence of improved survival in association with ICI treatment compared with BSC in patients with uHCC with CP-B liver dysfunction.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by genomic aberrations in oncogenes, cytogenetic abnormalities, and an aberrant epigenetic landscape. Nearly 50% of AML cases will relapse with current treatment. A major source of therapy resistance is the interaction of mesenchymal stroma with leukemic cells resulting in therapeutic protection. We aimed to determine pro-survival/anti-apoptotic protein networks involved in the stroma protection of leukemic cells. Proteomic profiling of cultured primary AML (n= 14) with Hs5 stroma cell line uncovered an up-regulation of energy-favorable metabolic proteins. Next, we modulated stroma-induced drug resistance with an epigenetic drug library, resulting in reduced apoptosis with histone deacetylase inhibitor (HDACi) treatment versus other epigenetic modifying compounds. Quantitative phosphoproteomic probing of this effect further revealed a metabolic-enriched phosphoproteome including significant up-regulation of acetyl-coenzyme A synthetase (ACSS2, S30) in leukemia-stroma HDACi treated cocultures compared with untreated monocultures. Validating these findings, we show ACSS2 substrate, acetate, promotes leukemic proliferation, ACSS2 knockout in leukemia cells inhibits leukemic proliferation and ACSS2 knockout in the stroma impairs leukemic metabolic fitness. Finally, we identify ACSS1/ACSS2-high expression AML subtype correlating with poor overall survival. Collectively, this study uncovers the leukemia-stroma phosphoproteome emphasizing a role for ACSS2 in mediating AML growth and drug resistance.

In his December cover story, the Ontario ER doctor Alan Drummond wrote about the overcrowding and underfunding in Canadian emergency departments. His candour and clarity earned a swell of admiration [...]

This serial issue is devoted to examining the artists of Germany, their cultural economy, and their increasing dependence on public agencies for support. The prospects for the up-and-coming generation of artists are examined and the available training institutions, teaching staff, study programs and qualifications for professional prospects and career opportunities. Articles include: (1) "Professional Artistic Training in Germany: An Introduction" (Andreas Joh. Wiesand); (2) "Training at Colleges of Art" (Carl Friedrich Schroer); and (3) "Training at Colleges of Music" (Werner Schulze-Reimpell). (EH)

At the Central Institute for Engineering, electronics, and Analytics (ZEA-1 by its acronym in German) of the Jülich Research Center GmbH, a cryostat was developed for the European Spallation Neutron Source (ESS) and manufactured from a titanium-stabilized austenitic stainless steel alloy (EN 1.4571). After tungsten inert gas welding, the welds exhibited a black, patchy discoloration. After materialographic preparation, the phenomena were examined using microscopic methods to assess their impact on the strength of the weld and thus on the usability of the cryostat. Not only could the impact on the cryostat operation be assessed, but the formation mechanism could be elucidated and suitable measures could be outlined to avoid the black, patchy discoloration.

The Perdew–Zunger (PZ) self-interaction correction (SIC) is an established tool to correct unphysical behavior in density functional approximations. Yet, the PZ-SIC is well-known to sometimes break molecular symmetries. An example of this is the benzene molecule, for which the PZ-SIC predicts a symmetry-broken electron density and molecular geometry, since the method does not describe the two possible Kekulé structures on an even footing, leading to local minima [Lehtola et al. J. Chem. Theory Comput.2016, 12, 3195]. The PZ-SIC is often implemented with Fermi–Löwdin orbitals (FLOs), yielding the FLO-SIC method, which likewise has issues with symmetry breaking and local minima [Trepte et al. J. Chem. Phys.2021, 155, 224109]. In this work, we propose a generalization of the PZ-SIC─the ensemble PZ-SIC (E-PZ-SIC) method─which shares the asymptotic computational scaling of the PZ-SIC (albeit with an additional prefactor). The E-PZ-SIC is straightforwardly applicable to various molecules, merely requiring one to average the self-interaction correction over all possible Kekulé structures, in line with chemical intuition. We showcase the implementation of the E-PZ-SIC with FLOs, as the resulting E-FLO-SIC method is easy to realize on top of an existing implementation of the FLO-SIC. We show that the E-FLO-SIC indeed eliminates symmetry breaking, reproducing a symmetric electron density and molecular geometry for benzene. The ensemble approach suggested herein could also be employed within approximate or locally scaled variants of the PZ-SIC and its FLO-SIC versions.

Conduct disorder is associated with the highest burden of any mental disorder in childhood, yet its neurobiology remains unclear. Inconsistent findings limit our understanding of the role of brain structure alterations in conduct disorder. This study aims to identify the most robust and replicable brain structural correlates of conduct disorder.

There is limited information on the mode of arrhythmia initiation in idiopathic ventricular fibrillation (IVF). A non–pause-dependent mechanism has been suggested to be the rule.

Over the course of four decades, model predictive control (MPC) has become one of the great success stories in systems and control. It has grown from its native habitat (chemical process control) into all domains of control applications—power and energy systems, mechatronics and robotics, as well as aerospace and aeronautics. Hence, in a modern systems and control curriculum, MPC triggers not so much the question of if it should be taught. In fact, industrial demand for and the continued research potential of MPC suggest that one should rather ask the Aristotelian 5W1H (what, when, where, why, who, and how?) about teaching MPC. This article presents insights into the 5Ws distilled from the results of a survey on teaching MPC conducted in the systems and control community. Moreover, the how is approached through blueprint suggestions for curricula for an undergraduate discrete-time linear-quadratic MPC course and for graduate courses covering the continuous-time nonlinear avenue and the learning-based route.