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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.

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

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.

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].

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.

Background Light transmission aggregometry (LTA) is considered the gold standard for the evaluation of platelet function but is labor-intensive and involves numerous manual steps. Automation may contribute to standardization. Here, we evaluate the performance characteristics of a new automated instrument, Thrombomate XRA (TXRA), and compare it against a manual instrument (PAP-8). Materials and Methods Leftover blood samples from blood donors or patients were tested in parallel with identical reagents and in identical concentrations both manually using PAP-8 and automated on the TXRA. In addition to precision and method comparison, an additional evaluation was performed on the TXRA against “virtual” platelet-poor plasma (VPPP) based on artificial intelligence. The main focus was on comparing the maximum aggregation (MA%) values. Results Precision for MA% ranged from 1.4 to 4.6% on TXRA for all reagents. Normal ranges for 100 healthy blood donors on both instruments were in a similar range for all reagents, with a tendency to slightly higher values with TXRA. Most agonists resulted in normally distributed MA%. Comparing 47 patient samples on both devices showed a good correlation for both slope and MA% with some differences in individual samples with epinephrine and TRAP. Correlation between the TXRA measurement against PPP and “virtual” PPP demonstrated excellent correlation. Reaction signatures of both devices were very similar. Conclusion TXRA provides reproducible LTA results that correlate with an established manual method when tested against PPP or VPPP. Its ability to perform LTA only from platelet-rich plasma without requiring autologous PPP simplifies LTA. TXRA is an important step not only for further standardizing LTA but also for a more widespread use of this important method.

Abstract The goal of this study is to compare the construct stability of long segmental dorsal stabilization in unstable midthoracic osteoporotic fractures with complete pedicle screw cement augmentation (ComPSCA) versus restricted pedicle screw cement augmentation (ResPSCA) of the most cranial and caudal pedicle screws under cyclic loading. Twelve fresh frozen human cadaveric specimens (Th4–Th10) from individuals aged 65 years and older were tested in a biomechanical cadaver study. All specimens received a DEXA scan and computer tomography (CT) scan prior to testing. All specimens were matched into pairs. These pairs were randomized into the ComPSCA group and ResPSCA group. An unstable Th7 fracture was simulated. Periodic bending in flexion direction with a torque of 2.5 Nm and 25,000 cycles was applied. Markers were applied to the vertebral bodies to measure segmental movement. After testing, a CT scan of all specimens was performed. The mean age of the specimens was 87.8 years (range 74–101). The mean T-score was − 3.6 (range − 1.2 to − 5.3). Implant failure was visible in three specimens, two of the ComPSCA group and one of the ResPSCA group, affecting only one pedicle screw in each case. Slightly higher segmental movement could be evaluated in these three specimens. No further statistically significant differences were observed between the study groups. The construct stability under cyclic loading in flexion direction of long segmental posterior stabilization of an unstable osteoporotic midthoracic fracture using ResPSCA seems to be comparable to ComPSCA.

Abstract Introduction Osteoporotic vertebral compression fractures (VCFs) are common. An increase in mortality associated with osteoporotic VCFs has been well documented. The purpose of this study was to assess the impact of time to surgery on 1-year survival in patients with osteoporotic vertebral compression fractures. Methods In a retrospective cohort study with prospective mortality follow-up, consecutive patients aged ≥ 60 years who had operative treatment of a low-energy fracture of a thoracolumbar vertebra and had undergone surgical stabilization between January 2015 and December 2018 were identified from our institutional database. By chart review, additional information on hospitalization time, comorbidities (expressed as ASA - American Society of Anesthesiologists Scale), complications and revision surgery was obtained. Time-to-surgery was defined as the time between admission and surgery. Mortality data was assessed by contacting the patients by phone, mail or the national social insurance database. Results Two hundred sixty patients (mean age 78 years, SD 7 years, range, 60 to 93; 172 female) were available for final analysis. Mean follow-up was 40 months (range, 12 to 68 months). Fifty-nine patients (22.7%) had died at final follow-up and 27/260 patients (10.4%) had died within 1 year after the surgery. Time-to-surgery was not different for patients who died within 1 year after the surgery and those who survived (p = .501). In-hospital complications were seen in 40/260 (15.4%) patients. Time-to-surgery showed a strong correlation with hospitalization time (Pearson’s r = .614, p

Abstract Objectives Osteoporotic fractures of the pelvis (OFP) are an increasing issue in orthopedics. Current classification systems (CS) are mostly CT-based and complex and offer only moderate to substantial inter-rater reliability (interRR) and intra-rater reliability (intraRR). MRI is thus gaining importance as a complement. This study aimed to develop a simple and reliable CT- and MRI-based CS for OFP. Methods A structured iterative procedure was conducted to reach a consensus among German-speaking spinal and pelvic trauma experts over 5 years. As a result, the proposed OF-Pelvis CS was developed. To assess its reliability, 28 experienced trauma and orthopedic surgeons categorized 25 anonymized cases using X-ray, CT, and MRI scans twice via online surveys. A period of 4 weeks separated the completion of the first from the second survey, and the cases were presented in an altered order. While 13 of the raters were also involved in developing the CS (developing raters (DR)), 15 user raters (UR) were not deeply involved in the development process. To assess the interRR of the OF-Pelvis categories, Fleiss’ kappa (κF) was calculated for each survey. The intraRR for both surveys was calculated for each rater using Kendall’s tau (τK). The presence of a modifier was calculated with κF for interRR and Cohen’s kappa (κC) for intraRR. Results The OF-Pelvis consists of five subgroups and three modifiers. Instability increases from subgroups 1 (OF1) to 5 (OF5) and by a given modifier. The three modifiers can be assigned alone or in combination. In both surveys, the interRR for subgroups was substantial: κF = 0.764 (Survey 1) and κF = 0.790 (Survey 2). The interRR of the DR and UR was nearly on par (κF Survey 1/Survey 2: DR 0.776/0.813; UR 0.748/0.766). The agreement for each of the five subgroups was also strong (κF min.–max. Survey 1/Survey 2: 0.708–0.827/0.747–0.852). The existence of at least one modifier was rated with substantial agreement (κF Survey 1/Survey 2: 0.646/0.629). The intraRR for subgroups showed almost perfect agreement (τK = 0.894, DR: τK = 0.901, UR: τK = 0.889). The modifier had an intraRR of κC = 0.684 (DR: κC = 0.723, UR: κC = 0.651), which is also considered substantial. Conclusion The OF-Pelvis is a reliable tool to categorize OFP with substantial interRR and almost perfect intraRR. The similar reliabilities between experienced DRs and URs demonstrate that the training status of the user is not important. However, it may be a reliable basis for an indication of the treatment score.

Antigen banks have been established to supply foot-and-mouth disease virus (FMDV) vaccines at short notice to respond to incursions or upsurges in cases of FMDV infection. Multiple vaccine strains are needed to protect against specific FMDV lineages that circulate within six viral serotypes that are unevenly distributed across the world. The optimal selection of distinct antigens held in a bank must carefully balance the desire to cover these risks with the costs of purchasing and maintaining vaccine antigens. PRAGMATIST is a semi-quantitative FMD vaccine strain selection tool combining three strands of evidence: (1) estimates of the risk of incursion from specific areas (source area score); (2) estimates of the relative prevalence of FMD viral lineages in each specific area (lineage distribution score); and (3) effectiveness of each vaccine against specific FMDV lineages based on laboratory vaccine matching tests (vaccine coverage score). The output is a vaccine score, which identifies vaccine strains that best address the threats, and consequently which are the highest priority for inclusion in vaccine antigen banks. In this paper, data used to populate PRAGMATIST are described, including the results from expert elicitations regarding FMD risk and viral lineage circulation, while vaccine coverage data is provided from vaccine matching tests performed at the WRLFMD between 2011 and 2021 (n = 2,150). These data were tailored to working examples for three hypothetical vaccine antigen bank perspectives (Europe, North America, and Australia). The results highlight the variation in the vaccine antigens required for storage in these different regions, dependent on risk. While the tool outputs are largely robust to uncertainty in the input parameters, variation in vaccine coverage score had the most noticeable impact on the estimated risk covered by each vaccine, particularly for vaccines that provide substantial risk coverage across several lineages.

We have recently introduced a novel approach to time-resolved cryo-electron microscopy (cryo-EM) that affords microsecond time resolution. It involves melting a cryo sample with a laser beam to allow dynamics of the embedded particles to occur. Once the laser beam is switched off, the sample revitrifies within just a few microseconds, trapping the particles in their transient configurations, which can subsequently be imaged to obtain a snap shot of the dynamics at this point in time. While we have previously performed such experiments with a modified transmission electron microscope, we here demonstrate a simpler implementation that uses an optical microscope. We believe that this will make our technique more easily accessible and hope that it will encourage other groups to apply microsecond time-resolved cryo-EM to study the fast dynamics of a variety of proteins.

The large number of interactions in nanoscale systems leads to the emergence of complex behavior. Understanding such complexity requires atomic-resolution observations with a time resolution that is high enough to match the characteristic timescale of the system. Our laboratory’s method of choice is time-resolved electron microscopy. In particular, we are interested in the development of novel methods and instrumentation for high-speed observations with atomic resolution. Here, we present an overview of the activities in our laboratory.

SARS-CoV-2 serosurveillance is important to adapt infection control measures and estimate the degree of underreporting. Blood donor samples can be used as a proxy for the healthy adult population. In a repeated cross-sectional study from April 2020 to April 2021, September 2021, and April/May 2022, 13 blood establishments collected 134,510 anonymised specimens from blood donors in 28 study regions across Germany. These were tested for antibodies against the SARS-CoV-2 spike protein and nucleocapsid, including neutralising capacity. Seroprevalence was adjusted for test performance and sampling and weighted for demographic differences between the sample and the general population. Seroprevalence estimates were compared to notified COVID-19 cases. The overall adjusted SARS-CoV-2 seroprevalence remained below 2% until December 2020 and increased to 18.1% in April 2021, 89.4% in September 2021, and to 100% in April/May 2022. Neutralising capacity was found in 74% of all positive specimens until April 2021 and in 98% in April/May 2022. Our serosurveillance allowed for repeated estimations of underreporting from the early stage of the pandemic onwards. Underreporting ranged between factors 5.1 and 1.1 in the first two waves of the pandemic and remained well below 2 afterwards, indicating an adequate test strategy and notification system in Germany.

The title compound, 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethanol monosolvate, C16H16N2O3S·C2H6O, (I), displays intermolecular O—H...O and O—H...N bonds in which the carboxyl group of the febuxostat molecule and the hydroxyl group of the ethanol molecule serve as hydrogen-bond donor sites. These interactions result in a helical hydrogen-bonded chain structure. The title structure is isostructural with a previously reported methanol analogue.

Abstract Background The purpose of this retrospective cohort study was to compare treatment strategies of two level-one trauma centers regarding clinical and radiological outcomes focusing on non-osteoporotic AOSpine type A3 fractures of the thoracolumbar spine at levels T11 to L2. Methods Eighty-seven patients between 18 and 65 years of age that were treated operatively in either of two trauma centers were included. One treatment strategy includes open posterior stabilization whereas the other uses percutaneous posterior stabilization. Both included additional anterior fusion if necessary. Demographic data, McCormack classification, duration of surgery, hospital stay and further parameters were assessed. Owestry Disability Index (ODI), Visual Analog Scale (VAS) and SF-36 were measured for functional outcome. Bisegmental kyphosis angle, reduction loss and sagittal alignment parameters were assessed for radiological outcome. Follow up was at least 24 months. Results There was no significant difference regarding our primary functional outcome parameter (ODI) between both groups. Regarding radiological outcome kyphosis angle at time of follow up did not show a significant difference. Reduction loss at time of follow up was moderate in both groups with a significantly lower rate in the percutaneously stabilized group. Surgery time was significantly shorter for posterior stabilization and anterior fusion in the percutaneous group. Time of hospital stay was equal for posterior stabilization but shorter for anterior fusion in the open stabilized group. Conclusion Both treatment strategies are safe and effective showing only minor loss of reduction. Clinical relevant differences in functional and radiographic outcome between the two surgical groups could not be demonstrated. Trial registration It was conducted according to ICMJE guidelines and has been retrospectively registered with the German Clinical Trials Registry (identification number: DRKS00015693, 07.11.2018).

Abstract Introduction Hybrid stabilization is an accepted therapy strategy for unstable osteoporotic thoracolumbar fractures. However, a moderate reduction loss has been reported and it remains unclear which anatomic structure is responsible for the reduction loss. Methods This retrospective study was performed at a level I trauma center. Patients aged 61 and older were stabilized using hybrid stabilization after suffering acute and unstable osteoporotic vertebral body fractures at the thoracolumbar spine. Posterior stabilization was done short-segmental and minimal invasive with cement-augmentation of all pedicle screws. The minimum follow-up has been 2 years. The outcome parameters were the reduction loss and the relative loss of height of both intervertebral discs adjacent to the fractured vertebral body, the fractured vertebral body and a reference disc (intervertebral disc superior of the stabilization) between the postoperative and latest lateral radiographs. Additionally, implant positioning and loosening was analyzed. Results 29 mainly female (72%) patients (73.3 ± 6.0 years) were included. Fractures consisted of 26 incomplete burst fractures and 3 complete burst fractures of the thoracolumbar junction (Th11 – L2: 86%) and the midlumbar spine. The mean follow-up time was 36 months (range: 24–58 months). The mean reduction loss was 7.7° (range: 1–25). The relative loss of heights of both intervertebral discs adjacent to the fractured vertebral body, the reference disc, and the central vertebral body were significant. Thereby, the relative loss of the superior disc height was significant higher compared to the reference disc. Additionally, only the relative loss of central vertebral body height and reduction loss correlated significantly. There were no signs of implant loosening in any patient. Conclusions The mean reduction loss was moderate 3 years after hybrid stabilization of unstable osteoporotic vertebral fractures of the thoracolumbar spine. A significant loss of both adjacent disc heights and the central vertebral body was seen, with the highest loss in the superior adjacent disc significantly outranging the reference disc. The superior adjacent intervertebral disc and the central part of the fractured vertebral body seem to be responsible for the majority of reduction loss.

Exposure to ozone (O _3 ) is associated with many human health problems, resulting in tens of thousands of premature deaths annually in Europe. This study quantifies the impact of changes in anthropogenic emissions of O _3 precursors on premature deaths from long-term O _3 exposure in Europe and the impact of emissions changes during 2005–2015 using the nested-grid chemical transport model Goddard Earth Observing System (GEOS)-Chem and its adjoint. In 2015, it is estimated that a 20% decrease in total anthropogenic emissions in our modeled European domain could prevent 1576 (467–3252) premature deaths from respiratory disease ( $ \unicode{x2A7E} $ 30 years of age), 70% of which is owing to the decrease in nitrogen oxides (NO _x ) emissions. Underlying this aggregate effect is substantial spatial variation. In most of Europe, O _3 formation is NO _x -limited so that NO _x emission reductions help to decrease premature deaths. Yet where O _3 formation is NO _x -saturated (as in parts of the United Kingdom, Benelux and Germany) emission reductions cause more premature deaths through increased ozone exposure. Despite the overall decreases in anthropogenic emissions, the marginal benefit, expressed as the avoided premature deaths per 1 kg km ^−2 yr ^−1 reduction in NO _x emissions, is found to generally increase during 2005–2015, with a mean value more than doubling over Europe. This highlights the general trend that O _3 formation becomes less sensitive to volatile organic compound emissions and more limited by NO _x emissions. An important policy implication of increasing marginal benefits is that more costly regulations of NO _x emissions are economically justified even as total anthropogenic emission are declining. NO _x contributions from road transport, industry, energy, and residential sectors are most affected by the change in the O _3 production regime. Consequently, European regulations of NO _x emissions targeted at those sectors will yield the highest health benefits per unit NO _x emission of all sources.

The neutron capture cross section of 241Am is an important quantity for nuclear energy production and fuel cycle scenarios. Several measurements have been performed in recent years with the aim to reduce existing uncertainties in evaluated data. Two previous measurements, performed at the 185 m flight-path station EAR1 of the neutron time-of-flight facility n_TOF at CERN, have permitted to substantially extend the resolved resonance region, but suffered in the near-thermal energy range from the unfavorable signal-to-background ratio resulting from the combination of the high radioactivity of 241Am and the rather low thermal neutron flux. The here presented 241Am(n,γ) measurement, performed with C6D6 liquid scintillator gamma detectors at the 20 m flight-path station EAR2 of the n_TOF facility, took advantage of the much higher neutron flux. The current status of the analysis of the data, focussed on the low-energy region, will be described here.

Accurate neutron capture cross section data for minor actinides (MAs) are required to estimate the production and transmutation rates of MAs in light water reactors, critical fast reactors like Gen-IV systems, and other innovative reactor systems such as accelerator driven systems (ADS). In particular, 244Cm, 246Cm and 248Cm play a role in the transport, storage and transmutation of the nuclear waste of the current nuclear reactors, due to the contribution of these isotopes to the radiotoxicity, neutron emission, and decay heat in the spent nuclear fuel. Also, capture reactions in these Cm isotopes open the path for the formation of heavier elements. In this work, the results of the capture cross section measurement on 244Cm, 246Cm and 248Cm performed at the CERN n_TOF facility are presented. It is important to notice that the Cm samples used in the experiment at n_TOF have been used previously in an experiment at J-PARC, this experiment and the previous one done in the 70s with a nuclear explosion were the only previous capture experiments for these isotopes. At n_TOF, the capture cross section measurements of 244Cm, 246Cm and 248Cm were performed at the 20 m vertical flight path (EAR2) with three C6D6 total energy detectors. In addition, the cross section of 244Cm was measured at the 185 m flight path (EAR1) with a Total Absorption Calorimeter (TAC). The combination of measurements in EAR1 and EAR2 has contributed to controlling and reducing the systematic uncertainties in the results. The compatibility of the different measurements performed and the techniques to obtain the results are presented in this paper as well as the procedure to obtain the resonance parameters.

Neutron capture cross section measurements of isotopes close to s-process branching-points are of fundamental importance for the understanding of this nucleosynthesis mechanism through which about 50% of the elements heavier than iron are produced. We present in this contribution the results corresponding to the high resolution measurement, for first time ever, of the 80Se(n, γ) cross section, in which 98 resonances never measured before have been reported. As a consequence, ten times more precise values for the MACS have been obtained compared to previous accepted value adopted in the astrophysical KADoNiS data base.

Atypical teratoid/rhabdoid tumors (AT/RT) are aggressively growing malignant embryonal neoplasms of the central nervous system (CNS), which mainly affect young children. Loss of SMARCB1/INI1 (or SMARCA4 in rare cases) is recognized as the genetic hallmark of AT/RTs and these tumors can be distinguished into three distinct DNA-methylation based molecular subgroups (i.e. -MYC, -SHH and -TYR). While most AT/RTs are considered to occur de novo, previous studies have recognized secondary SMARCB1/INI1-deficient rhabdoid tumors arising from other low grade CNS tumors in young patients. Three AT/RTs, which harbor epigenetic and mutational characteristics of pleomorphic xanthoastrocytoma (PXA), while being entirely void of nuclear SMARCB1/INI1 expression, were recently described in older children. We here report the first case of an AT/RT with molecular features of PXA in a senior patient.

The dynamics of proteins that are associated with their function typically occur on the microsecond timescale, orders of magnitude faster than the time resolution of cryo-electron microscopy. We have recently introduced a novel approach to time-resolved cryo-electron microscopy that affords microsecond time resolution. It involves melting a cryo sample with a heating laser, so as to allow dynamics of the proteins to briefly occur in the liquid phase. When the laser is turned off, the sample rapidly revitrifies, trapping the particles in their transient configurations. Precise control of the temperature evolution of the sample is crucial for such an approach to succeed. Here, we provide a detailed characterization of the heat transfer occurring under laser irradiation as well as the associated phase behavior of the cryo sample. While areas close to the laser focus undergo melting and revitrification, surrounding regions crystallize. In situ observations of these phase changes therefore provide a convenient approach for assessing the temperature reached in each melting and revitrification experiment and for adjusting the heating laser power on the fly.

Vaccine-induced thrombotic thrombocytopenia (VITT), or thrombosis with thrombocytopenia syndrome (TTS), is a rare but serious complication of adenovirus-based vaccines against severe respiratory syndrome coronavirus 2 (SARS-CoV-2). Observation of long-term outcomes is important to guide treatment of affected patients. This single-center consecutive cohort study included all patients diagnosed based on (1) vaccination 4 to 21 days before symptom onset, (2) signs or symptoms of venous or arterial thrombosis, (3) thrombocytopenia < 150/nL, (4) positive anti-platelet factor 4 (PF4) antibody, and (5) elevated D-Dimer > 4 times the upper limit of normal. Nine patients were enrolled. Acute management consisted of parenteral anticoagulants, corticosteroids, intravenous immunoglobulin (IVIG), and/or eculizumab. Eculizumab was successfully used in two patients with recurrent thromboembolic events after IVIG. Direct oral anticoagulants were given after hospital discharge. Median follow-up duration was 300 days (range 153 to 380). All patients survived the acute phase of the disease and were discharged from hospital. One patient died from long-term neurological sequelae of cerebral venous sinus thrombosis 335 days after diagnosis. Eight out of nine patients were alive at last follow-up, and seven had fully recovered. Anti-PF4 antibodies remained detectable for at least 12 weeks after diagnosis, and D-Dimer remained elevated in some patients despite oral anticoagulation. No recurrent thromboembolic events, other signs of VITT relapse, or bleeding complications occurred after discharge. In conclusion, VITT appears to be a highly prothrombotic condition. IVIG is not always successful, and eculizumab may be considered a rescue agent. Long-term management with direct oral anticoagulants appears to be safe and effective.

The COVID-19 pandemic has resulted in significant morbidity and mortality worldwide. To prevent severe infection, mass COVID-19 vaccination campaigns with several vaccine types are currently underway. We report pathological and immunological findings in 8 patients who developed vaccine-induced immune thrombotic thrombocytopenia (VITT) after administration of SARS-CoV-2 vaccine ChAdOx1 nCoV-19. We analyzed patient material using enzyme immune assays, flow cytometry and heparin-induced platelet aggregation assay and performed autopsies on two fatal cases. Eight patients (5 female, 3 male) with a median age of 41.5 years (range, 24 to 53) were referred to us with suspected thrombotic complications 6 to 20 days after ChAdOx1 nCoV-19 vaccination. All patients had thrombocytopenia at admission. Patients had a median platelet count of 46.5 x109/L (range, 8 to 92). Three had a fatal outcome and 5 were successfully treated. Autopsies showed arterial and venous thromboses in various organs and the occlusion of glomerular capillaries by hyaline thrombi. Sera from VITT patients contain high titer antibodies against platelet factor 4 (PF4) (OD 2.59±0.64). PF4 antibodies in VITT patients induced significant increase in procoagulant markers (P-selectin and phosphatidylserine externalization) compared to healthy volunteers and healthy vaccinated volunteers. The generation of procoagulant platelets was PF4 and heparin dependent. We demonstrate the contribution of antibody-mediated platelet activation in the pathogenesis of VITT.

The economic principle of communication, according to which successful communication can be reached by least effort, has been studied for verbal communication. With respect to nonverbal behavior, it implies that forms of iconic gestures change over the course of communication and become reduced in the sense of less pronounced. These changes and their effects on learning are currently unexplored in relevant literature. Addressing this research gap, we conducted a word learning study to test the effects of changing gestures on children’s slow mapping. We applied a within-subject design and tested 51 children, aged 6.7 years (SD = 0.4), who learned unknown words from a story. The storyteller acted on the basis of two conditions: In one condition, in which half of the target words were presented, the story presentation was enhanced with progressively reduced iconic gestures (PRG); in the other condition, half of the target words were accompanied by fully executed iconic gestures (FEG). To ensure a reliable gesture presentation, children were exposed to a recorded person telling a story in both conditions. We tested the slow mapping effects on children’s productive and receptive word knowledge three minutes as well as two to three days after being presented the story. The results suggest that children’s production of the target words, but not their understanding thereof, was enhanced by PRG.

The rapid growth of the field of time-resolved and ultrafast electron microscopy has been accompanied by the active development of new instrumentation. Recently, time-resolved microscopes equipped with a field emission gun have been introduced, demonstrating great potential for experiments that benefit from the high brightness and coherence of the electron source. Here, we describe a straightforward design of a time-resolved transmission electron microscope with a Schottky field emission gun and characterize its performance. At the same time, our design gives us the flexibility to alternatively operate the instrument as if it was equipped with a flat metal photocathode. We can, thus, effectively choose to sacrifice brightness in order to obtain pulses with vastly larger numbers of electrons than from the emitter if for a given application the number of electrons is a crucial figure of merit. We believe that our straightforward and flexible design will be of great practical relevance to researchers wishing to enter the field.

The manipulation of liquids at nanoscale dimensions is a central goal of the emergent nanofluidics field. Such endeavors extend to nanodroplets, which are ubiquitous objects involved in many technological applications. Here, we employ time-resolved electron microscopy to elucidate the formation of so-called jumping nanodroplets on a graphene surface. We flash-melt a thin gold nanostructure with a laser pulse and directly observe how the resulting nanodroplet contracts into a sphere and jumps off its substrate, a process that occurs in just a few nanoseconds. Our study provides the first experimental characterization of these morphological dynamics through real-time observation and reveals new aspects of the phenomenon. We observe that friction alters the trajectories of individual droplets. Surprisingly, this leads some droplets to adopt dumbbell-shaped geometries after they jump, suggesting that they spin with considerable angular momentum. Our experiments open up new avenues for studying and controlling the fast morphological dynamics of nanodroplets through their interaction with structured surfaces.

Current theories of psychosis highlight the role of abnormal learning signals, i.e., prediction errors (PEs) and uncertainty, in the formation of delusional beliefs. We employed computational analyses of behaviour and functional magnetic resonance imaging (fMRI) to examine whether such abnormalities are evident in clinical high risk (CHR) individuals.Non-medicated CHR individuals (n = 13) and control participants (n = 13) performed a probabilistic learning paradigm during fMRI data acquisition. We used a hierarchical Bayesian model to infer subject-specific computations from behaviour – with a focus on PEs and uncertainty (or its inverse, precision) at different levels, including environmental ‘volatility’ – and used these computational quantities for analyses of fMRI data.Computational modelling of CHR individuals’ behaviour indicated volatility estimates converged to significantly higher levels than in controls. Model-based fMRI demonstrated increased activity in prefrontal and insular regions of CHR individuals in response to precision-weighted low-level outcome PEs, while activations of prefrontal, orbitofrontal and anterior insula cortex by higher-level PEs (that serve to update volatility estimates) were reduced. Additionally, prefrontal cortical activity in response to outcome PEs in CHR was negatively associated with clinical measures of global functioning.Our results suggest a multi-faceted learning abnormality in CHR individuals under conditions of environmental uncertainty, comprising higher levels of volatility estimates combined with reduced cortical activation, and abnormally high activations in prefrontal and insular areas by precision-weighted outcome PEs. This atypical representation of high- and low-level learning signals might reflect a predisposition to delusion formation.

Most elements heavier than iron have been generated in the stellar media by means of neutron capture reactions, approximately half are produced by the slow neutron capture or s-process. Radiative neutron capture cross section measurements are of fundamental importance for the study of this mechanism. In this contribution we present a brief summary on the measurement and results for the 80Se(n,γ) cross-section. The experiment was carried out at CERN n_TOF EAR1 via the time of flight (ToF) technique, using four C6D6 scintillation detectors with very fast response. More than a hundred new resonances have been analyzed for the first time with a high accuracy. The MACS obtained at kT = 8 keV is 36% smaller than the recommended value in KADo-NiS. Some of the astrophysical implications of this result are elucidated in this contribution.

In the salt (5α,6α)-6-[(2,5,8,11,14,17,20-heptaoxadocosan-22-yl)oxy]-3,14-dihydroxy-17-(prop-2-en-1-yl)-4,5-epoxymorphinan-17-ium hydrogen oxalate, C34H54NO11+·C2HO4− the polyether unit of the naloxegol cation adopts the shape of a squashed open letter `O'. In the crystal, the hydrogen oxalate anions are linked into a chain by O—H...O hydrogen bonds. Each naloxegol unit is hydrogen bonded to three hydrogen oxalate ions via two O—H...O and one N—H...O interactions. The resulting hydrogen-bonded two-dimensional layer structure is 3,5-connected and has the 3,5 L50 topology.

The molecule of buthalital, (I) [systematic name: 5-(2-methylpropyl)-5-(prop-2-en-1-yl)-2-sulfanylidene-1,3-diazinane-4,6-dione], C11H16N2O2S, exhibits a planar pyrimidine ring, whereas the pyrimidine ring of methitural, (II) [systematic name: 5-(1-methylbutyl)-5-[2-(methylsulfanyl)ethyl]-2-sulfanylidene-1,3-diazinane-4,6-dione], C12H20N2O2S2, is slightly puckered. (I) and (II) contain the same hydrogen-bonded chain structure in which each molecule is connected, via four N—H...O=C hydrogen bonds, to two other molecules, resulting in a hydrogen-bonded chain displaying a sequence of R22(8) rings. The same type of N—H...O=C hydrogen-bonded chain has previously been found in several 5,5-disubstituted derivatives of barbituric acid which are chemically closely related to (I) and (II).

Platelet autoantibody-induced platelet clearance represents a major pathomechanism in immune thrombocytopenia (ITP). There is growing evidence for clinical differences between anti-glycoprotein IIb/IIIa and anti-glycoprotein Ib/IX mediated ITP. Glycoprotein V is a well characterized target antigen in Varicella-associated and drug-induced thrombocytopenia. We conducted a systematic study assessing the prevalence and functional capacity of autoantibodies against glycoprotein V. A total of 1140 patients were included. In one-third of patients, platelet-bound autoantibodies against glycoproteins Ib/IX, IIb/IIIa, or V were detected in a monoclonal antibody immobilization of platelet antigen assay; platelet-bound autoantiglycoprotein V was present in the majority of samples (222 out of 343, 64.7%). Investigation of patient sera revealed the presence of free autoantibodies against glycoprotein V in 13.5% of these patients by an indirect monoclonal antibody immobilization of platelet antigen assay, but in 39.6% by surface plasmon resonance technology. These antibodies showed significantly lower avidity (association/dissociation ratio 0.32±0.13 vs. 0.73±0.14; P