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This paper identifies and addresses three key challenges in energy systems analysis—varying assumptions, computational limitations, and coverage of a few indicators only. First, results depend strongly on assumptions, i.e., varying input data. Hence, comparisons and robust results are hard to achieve. To address this, we use a broad range of possible inputs through an extensive literature review by scenario experts. Second, we overcome computational limitations using high-performance computing (HPC) and an automated workflow. Third, by coupling models and developing 13 indicators to evaluate the overall quality of energy systems in Germany for 2030, we include many aspects of security of supply, market impact, life cycle analysis and cost optimization. A cluster analysis of scenarios by indicators reveals three recognizable clusters, separating systems with a high share of renewables clearly from more conventional sets. Additionally, scenarios can be identified which perform very positive for many of the 13 indicators. We conclude that an automated, coupled workflow on supercomputers based on a broad parameter space is able to produce robust results for many important aspects of future energy systems. Since all models and software components are released as open-source, all components of a multi-perspective model-chain are now available to the energy system modeling community.

Background: Persons with acquired hemophilia A are often older and suffer from comorbidity or frailty. Little is known about the impact on clinically relevant outcomes of acquired hemophilia A. Objectives: To assess the relevance of age, physical performance status, comorbidity, and concomitant medication on the risk of bleeding and other outcomes. Methods: Post hoc analysis of data from the GTH-AHA-EMI study that used emicizumab for bleed protection and withheld immunosuppressive treatment during the early phase of management. Primary endpoint was the rate of clinically relevant new bleeding (CRNB) during the first 12 weeks of emicizumab prophylaxis. Results: Forty-seven patients were enrolled. Median age was 76 years; performance status (World Health Organization performance status [WHO-PS]) was 3 or worse in 41%; Charlson comorbidity index (CCI) was 5 or higher in 63%; antithrombotic drugs were reported in 34%. Rate of CRNB during 12 weeks of emicizumab prophylaxis was similar across subgroups of age, sex, WHO-PS, CCI, baseline factor VIII activity, and inhibitor titer. Patients with CRNB during the study had more severe anemia already at baseline. However, persistent severe anemia in week 4 was not related to risk of bleeding beyond this time. CRNB was associated with injury from falling in 7 of 14 patients. Adverse events grade 3 or higher were not related to baseline CCI or age but were more frequent in patients with poor WHO-PS. Conclusion: Emicizumab provided bleed protection regardless of age and comorbidity. Clinical baseline characteristics did not predict breakthrough bleeding under emicizumab. Poor WHO-PS at baseline was associated with severe adverse events during the study.

Immunoglobulins for intravenous use (IVIgs) and subcutaneous use (SCIgs) can prevent recurrent and severe infections in patients with secondary antibody deficiencies that are frequently linked to haematological/oncological malignancies as well as other clinical conditions and their respective treatments. Even so, as IVIgs and SCIgs are costly and their supply is limited, their clinical use must be optimised. The aim of this position paper is to provide structured practical guidance on the optimal use of IVIgs and SCIgs in secondary antibody deficiencies, particularly in haematological and oncological practice. The authors agree that the occurrence of severe infections is a prerequisite for the use of IVIgs. Serum IgG levels in general as well as IgG subclass levels can be additional indicators of whether a patient could benefit from IVIgs. Responsiveness to vaccines can help to identify immunodeficiency. Patients with chronic lymphocytic leukaemia or multiple myeloma who are receiving respective treatment, especially B-cell depletion therapy, but also some patients with autoimmune diseases are prone to antibody deficiencies and need IVIgs. For the optimal use of IVIgs and to maximise their potential benefit, the indication must be individually assessed for each patient. As a primary treatment goal, the authors define a sufficient prophylaxis of severe infections, which can be supported by normalising IgG levels. If the initiated treatment is insufficient or linked to intolerable adverse reactions, switching the product within the class of IVIgs or changing to a different batch of the same product can be considered. Pausing treatment can also be considered if there are no infections, which happens more frequently in summer, but treatment needs to be resumed once infections return. These structured recommendations for IVIg treatment in patients with secondary antibody deficiency may provide guidance for clinical practice and therefore help to allocate IVIgs to those who will benefit the most, without overusing valuable resources.

Abstract Context Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion, mostly induced by pituitary adenomas. The care of pregnant women with acromegaly is challenging, in part due to existing clinical data being limited and not entirely consistent with regard to potential risks for mother and child. Objective To retrospectively examine data on pregnancy and maternal as well as neonatal outcomes in patients with acromegaly. Design & methods Retrospective data analysis from 47 pregnancies of 31 women treated in centers of the German Acromegaly Registry. Results 87.1% of the studied women underwent transsphenoidal surgery before pregnancy. In 51.1% a combination of dopamine agonists and somatostatin analogs were used before pregnancy. Three women did not receive any therapy for acromegaly. During pregnancy only 6.4% received either somatostatin analogs or dopamine agonists. In total, 70.2% of all documented pregnancies emerged spontaneously. Gestational diabetes was diagnosed in 10.6% and gravid hypertension in 6.4%. Overall, no preterm birth was detected. Indeed, 87% of acromegalic women experienced a delivery without complications. Conclusion Pregnancies in women with acromegaly are possible and the course of pregnancy is in general safe for mother and child both with and without specific treatment for acromegaly. The prevalence of concomitant metabolic diseases such as gestational diabetes is comparable to the prevalence in healthy pregnant women. Nevertheless, larger studies with more data in pregnant patients with acromegaly are needed to provide safe and effective care for pregnant women with this condition.

Abstract Metalenses are flat lenses, where sub-wavelength, so-called meta-atoms manipulate the electric field to perform a given lens function. Compared to traditional lenses, the two main drawbacks of metalenses are their achromatic limitations and low efficiencies. While an abundance of simulations show that efficiencies above 90% are attainable for low numerical apertures (NA), experimental reports showing such high efficiencies are limited. Here, we use electron-beam lithography (EBL) to realize a set of lenses with varying NA from 0.08 to 0.93. The low NAs were expected to fit the model, and the higher NAs determine the validity range of the model. We find that measured efficiencies above 92% for NA = 0.24 are achievable, and that a slight modification of the simulation model extends its validility to NA = 0.6. Based on our results, we discuss that the lower efficiencies reported in the literature are caused by low-fidelity manufacturing, closing the efficiency gap between measurements and simulation in metalens fabrication.

Speckles are inherent in structured laser-based light projection using diffractive optics such as metasurfaces or diffractive optical elements (DOEs). One application of structured light is to provide illumination for machine vision and depth sensing. This is particularly attractive for mobile or low-power applications, where metasurfaces provide a compact, customizable solution, which can furthermore reach extreme field of illuminations. However, the speckles might limit detection capabilities by, e.g., lowering the detection range or providing false results. In this work, we present a series of measurements with matching simulations on a 70 × 50 degrees diffractive diffuser using different light sources (varying divergence angles + VCSEL array) to quantify the impact of speckles. We observe a qualitative agreement in speckle correlation between the measurements and the simulations and explain, in part using cross-correlation for analysis, why we do not observe the same speckle pattern between the measurements and the simulations. By performing extra simulations, we conclude that by only changing the light source, there is a limit to the reduction of the speckle contrast which, we can achieve, and, to reduce it further, alternative approaches such as changing the design method of the diffractive diffuser must be harnessed.

Abstract Observing proteins as they perform their tasks has largely remained elusive, which has left our understanding of protein function fundamentally incomplete. To enable such observations, we have recently proposed a technique that improves the time resolution of cryo-electron microscopy (cryo-EM) to microseconds. Here, we demonstrate that microsecond time-resolved cryo-EM enables observations of fast protein dynamics. We use our approach to elucidate the mechanics of the capsid of cowpea chlorotic mottle virus (CCMV), whose large-amplitude motions play a crucial role in the viral life cycle. We observe that a pH jump causes the extended configuration of the capsid to contract on the microsecond timescale. While this is a concerted process, the motions of the capsid proteins involve different timescales, leading to a curved reaction path. It is difficult to conceive how such a detailed picture of the dynamics could have been obtained with any other method, which highlights the potential of our technique. Crucially, our experiments pave the way for microsecond time-resolved cryo-EM to be applied to a broad range of protein dynamics that previously could not have been observed. This promises to fundamentally advance our understanding of protein function.

Water can be vitrified if it is cooled at high rates, which makes it possible to outrun crystallization in so-called no man's land, a range of deeply supercooled temperatures where water crystallizes rapidly. Here, we study the reverse process in pure water samples by flash melting amorphous ice with microsecond laser pulses. Time-resolved electron diffraction reveals that the sample transiently crystallizes despite a heating rate of more than 5 × 106 K/s, even though under the same conditions, vitrification can be achieved with a similar cooling rate of 107 K/s. Moreover, we observe different crystallization kinetics for amorphous solid water and hyperquenched glassy water. These experiments open up new avenues for elucidating the crystallization mechanism of water and studying its dynamics in no man's land. They also add important insights into the laser melting and revitrification processes that are integral to the emerging field of microsecond time-resolved cryo-electron microscopy. [ABSTRACT FROM AUTHOR]

Abstract Metamizole is an analgesic, antipyretic, and spasmolytic drug in Germany only approved for the treatment of severe pain or high fever that does not respond to other measures. In recent years, an increased use has been described among both adults and children, often against the approved indication. The most important side effect of metamizole is the development of agranulocytosis (neutrophil count

IntroductionDirect oral anticoagulants (DOACs) have become widely used in clinical practice for preventing thromboembolic events. Point-of-care testing methods, particularly those based on urine samples, offer a promising approach for rapid and accurate assessment of DOAC presence. This pilot study aims to evaluate the utility of a urine-based DOAC dipstick test as a point-of-care tool for identifying DOAB presence in acute ischemic stroke (AIS) or transient ischemic attack (TIA) patients.Patients and methodsThis prospective pilot study included patients with AIS/TIA eligible for DOAC-measurement. After exclusion of 3 patients, 23 patients with DOAC-intake (DOAC group; factor-Xa-inhibitors; n = 23) and 21 patients without DOAC-intake (control-group) remained for analyses. The urine-based DOAC dipstick test and parallel blood-based specific DOAC-level assessment were performed in all patients. Time-intervals of sampling urine/blood sampling and result of DOAC-test were recorded to analyze a potential time benefit based on dipstick evaluation.ResultsThe urine-based DOAC dipstick test demonstrated high sensitivity (100%) and specificity (100%), correctly identifying all patients with anticoagulatory activity due to DOAC intake (i.e., anti-Xalevel ≥30 ng/mL). Moreover, the visual readout of the test provided semiquantitative information on drug-specific anti-Xa levels, showing a sensitivity of 83% and specificity of 93% to detect anti-Xa levels ≥120 ng/mL. The dipstick test exhibited a median time-benefit of 2:25 h compared to standard blood-based DOAC-level testing.DiscussionThe results of this pilot study underline the efficacy of urine-based point-of-care testing as a rapid and reliable method for assessing DOAC presence in patients with acute ischemic stroke.ConclusionThe value of this tool for clinical decision-making in stroke management needs to be established in future trials.Clinical Trial Registration: Clinicaltrails.org identifier [NCT06037200].

Abstract A generally accepted understanding of the anomalous properties of water will only emerge if it becomes possible to systematically characterize water in the deeply supercooled regime, from where the anomalies appear to emanate. This has largely remained elusive because water crystallizes rapidly between 160 K and 232 K. Here, we present an experimental approach to rapidly prepare deeply supercooled water at a well-defined temperature and probe it with electron diffraction before crystallization occurs. We show that as water is cooled from room temperature to cryogenic temperature, its structure evolves smoothly, approaching that of amorphous ice just below 200 K. Our experiments narrow down the range of possible explanations for the origin of the water anomalies and open up new avenues for studying supercooled water.

CD177 is a glycosyl phosphatidyl inositol (GPI)-linked, neutrophil-specific glycoprotein that in 3–5% of normal individuals is absent from all neutrophils. The molecular mechanism behind the absence of CD177 has not been unravelled completely. Here, we analyse the impact of the recently described CD177 c.1291G>A variant on CD177 expression. Recombinant CD177 c.1291G>A was expressed in HEK293F cells and its expression on the cell surface, inside the cell, and in the culture supernatant was investigated. The CD177 c.1291G>A protein was characterised serologically and its interaction with proteinase 3 (PR3) was demonstrated by confocal laser scanning microscopy. Our experiments show that CD177 c.1291G>A does not interfere with CD177 protein biosynthesis but affects the membrane expression of CD177, leading to very low copy numbers of the protein on the cellular surface. The mutation does not interfere with the ability of the protein to bind PR3 or human polyclonal antibodies against wild-type CD177. Carriers of the c.1291G>A allele are supposed to be phenotyped as CD177-negative, but the protein is present in soluble form. The presence of CD177 c.1291A leads to the production of an unstable CD177 protein and an apparent “CD177-null” phenotype.

The two-component compound formed by codeine and cyclopentobarbital was produced using grinding techniques and through evaporation from alcoholic solutions. The cocrystal nature of this phase was established unequivocally through single crystal X-ray structure determination. The asymmetric unit contains one formula unit. In the cyclopentobarbital molecule, the cyclopentenyl ring is disordered over two positions related by a rotation of approximately 180° about its C—C bond to the pyrimidine ring. The two NH groups of the cyclopentobarbital molecule form N—H⋯N and N—H⋯O bonds to piperidine and hydroxyl groups, respectively, belonging to different codeine molecules. In addition, the hydroxyl and methoxy groups of neighboring codeine molecules are linked by O—H⋯O interactions, resulting in a H-bonded framework structure of codeine and cyclopentobarbital molecules. The cocrystal was also characterized using thermal analysis, X-ray powder diffraction and IR spectroscopy.

The title compound, 2,6-diamino-5-[(2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl)methyl]pyrimidin-1-ium methanesulfonate, C19H23N4O3+·CH3O3S−, is a salt made up from a protonated iclaprim molecule and a mesylate anion. The pyrimidine and chromene units of the iclaprim molecule form an orthogonal arrangement [interplanar angle of 89.67 (6)°], and the 3-nitrogen position of the pyrimidine ring is protonated. Four distinct N—H...O interactions and an additional N—H...N hydrogen bond connect iclaprim and mesylate molecules to one another, resulting in an infinite hydrogen-bonded molecular tape structure. The central section of the tape is formed by a sequence of fused hydrogen-bonded rings involving four distinct ring types.

Vacuum glazing products have been in development for the past decades. Such glazing products regularly feature two parallel glass panes that have a small, evacuated gap in their interstitial space. To maintain the vacuum and the form of the glass product, regularly vacuum tight edge seals and a grid of distance pillars are integrated. During the years of development, the major focus was set on the production and durability aspects of the glass products, but relatively few efforts had been conducted towards the integration of such glass products into window constructions. Employing typically used double- and triple glazing windows’ frames does not represent a feasible option. This is due to the specification given by vacuum glazing products, such as their small thickness and the requirement for sufficient glass edge coverage due to the major thermal bridge adjacent to the edge seal. The authors, together with major players from the window producing industry, started a R&D effort that targeted disruptive new concepts for vacuum glass windows. Four different designs were developed that not only integrated vacuum glass products, but also featured unusual opening patterns, the latest generation of electrically driven fitting products, and specific seals. The thermal and acoustical performance of the prototypes was improved during the development via employment of numeric thermal simulation and lab testing. The present contribution illustrates the four prototypes and their performance, which – for instance – pertaining to the UW-value is down to 0.6–0.7 W · m−2 · K−1 at a glass thickness of less than 1 cm.

Abstract Objectives The purpose of this study was to investigate whether the addition of computed tomography (CT) to magnetic resonance imaging (MRI) improves the accuracy of classifying osteoporotic vertebral body fractures (OVBF). Methods A retrospective analysis of a prospective single-center database has been performed. All consecutive patients who had suffered an acute thoracolumbar OVBF in one level II spine center between 2017 and 2019 were analyzed. Thereby, fractures of type OF 1 and OF 5 were excluded. All fractures were initially classified by 5 board-certified orthopaedic surgeons based on MRI and conventional radiographs. Afterwards a reclassification including CT scans were performed. Differences in OF classification and OF score values between both measurements were analyzed. Results A total of 61 patients were analyzed with a mean age 75.8 years (SD: 8.8 years). In 82.9% of the cases, there was no difference in OF classification comparing classification based only on MRI versus MRI + CT. A difference of more than two OF types was observed in less than 1% of all ratings. The inter-rater reliabilities of the OF classification based on CT + MRI and MRI alone were 0.63 and 0.49, respectively. In 97.5% of the cases there was no therapy-relevant difference of the treatment recommendation with respect of a surgical or nonoperative treatment recommendation based on the OF score. Conclusion In terms of the OF classification and the OF score, the addition of CT add limited value compared to conventional radiographs and MRI only. Additionally, there is only a minor rate of disagreement in treatment recommendations when adding a CT.

Little is known about the dynamics of human cooperation in groups with changing compositions. Using data from a large-scale and long-term online public goods game, this study shows how group changes are associated with temporarily lower cooperation.

In the isoxaflutole molecule {systematic name: (5-cyclopropyl-1,2-oxazol-4-yl)[2-(methylsulfonyl)-4-(trifluoromethyl)phenyl]methanone; C15H12F3NO4S}, the 1,2-oxazole and methanone fragments form an almost coplanar unit, whereas the methanone and phenyl mean planes are inclined by an angle of more than 60°. This conformation differs fundamentally from all other known examples of the 1,2-oxazol-4-yl(phenyl)methanone fragment and is ascribed to the presence of the bulky methylsulfonyl para substituent at the phenyl ring. PIXEL calculations reveal that the largest contributions to the stabilization of the crystal persist within a columnar arrangement of molecules along the twofold screw axis and in interactions between adjacent columns related by an inversion operation. Both these intra-column and inter-column motifs are dominated by the dispersion energy term but also display additional significant stabilization effects as a result of three short intermolecular C—H...O contacts involving the methanesulfonyl-O atoms.

Abstract We present a newly developed approach to characterize the sources of fine particulate matter (PM2.5)‐related premature deaths in Europe using the chemical transport model GEOS‐Chem and its adjoint. The contributions of emissions from each individual country, species, and sector are quantified and mapped out at km scale. In 2015, total PM2.5‐related premature death is estimated to be 449,813 (257,846–722,138) in Europe, 59.0% of which were contributed by domestic anthropogenic emissions. The anthropogenic emissions of nitrogen oxides, ammonia, and organic carbon contributed most to the PM2.5‐related health damages, making up 29.6%, 23.2%, and 16.8%, respectively of all domestic anthropogenic contributions. Residential, agricultural, and ground transport emissions are calculated to be the largest three sectoral sources of PM2.5‐related health risks, accounting for 23.5%, 23.0%, and 19.4%, respectively, of total anthropogenic contributions within Europe. After excluding the influence of extra‐regional sources, we find eastern European countries suffered from more premature deaths than their emissions caused; in contrast, the emissions from some central and western European regions contributed premature deaths exceeding three times the number of deaths that occurred locally. During 2005–2015, the first decade of PM2.5 regulation in Europe, emission controls reduced PM2.5‐related health damages in nearly all European countries, resulting in 63,538 (46,092–91,082) fewer PM2.5‐related premature deaths. However, our calculation suggests that efforts to reduce air pollution from key sectors in some countries can be offset by the lag in control of emissions in others. International cooperation is therefore vitally important for tackling air pollution and reducing corresponding detrimental effects on public health.