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Abstract Objectives To assess the prognostic value of cardiac MRI (CMR) parameters for the occurrence of major adverse cardiac events (MACE) in patients with infarct-like myocarditis. Methods In this retrospective single-center study, patients with CMR-confirmed acute myocarditis with infarct-like presentation were identified (2007–2020). Functional and structural parameters were analyzed including late gadolinium enhancement (LGE). The primary endpoint was the occurrence of MACE up to 5 years after discharge. Results In total, 130 patients (mean age, 40 ± 19 years; 97 men, 75%) with infarct-like myocarditis were included. CMR was conducted a median of 3 days (interquartile range [IQR], 1–5) after symptom onset. MACE occurred in 18/130 patients (14%) during a median follow-up of 19.3 months (IQR, 4.5–53). The median extent of LGE was 7% (IQR, 4–10). LGE affected the subepicardium in 111/130 patients (85%), the midwall in 45/130 patients (35%), and both the subepicardium and midwall in 27/130 patients (21%). Transmural extension of non-ischemic LGE lesions was observed in 15/130 patients (12%) and septal LGE in 42/130 patients (32%). In univariable Cox regression analysis, a significant association was found between the occurrence of MACE and both, quantified LGE extent and transmural LGE pattern. In multivariable analysis, transmural extension of LGE was an independent predictor for MACE (hazard ratio, 6.34; 95% confidence interval: 2.29–17.49; p

Abstract Background Increased levels of physical activity are associated with a reduction of breast cancer mortality, especially in postmenopausal women with positive hormone receptor status. So far, previous observational case–control and cohort studies have focused on associations between overall leisure time physical activity and survival of women with breast cancer in general. Methods In this multicenter prospective cohort study, conducted in Germany between 30th August 2012 to 29th December 2017, we investigated general physical activity in a homogenous sample of n = 1440 postmenopausal women with advanced (inoperable locally advanced or metastatic), hormone receptor-positive breast cancer receiving the same therapy (everolimus and exemestane). Self-reported physical activity was assessed using the Godin Leisure Time Exercise Questionnaire (GLTEQ) before and every 3 months during treatment. Participants were then classified into “active” and “insufficiently active” to screen their activity behavior the week prior to medical treatment. In addition, changes in physical activity patterns were assessed. Adjusted Cox regression analyses were performed for the activity categories to determine hazard ratios (HR). Besides progression-free survival (PFS), adverse events (AEs), QoL, and fatigue were assessed every 3 months until study termination. Results Compared to “insufficiently active” patients, “active” individuals indicated a significantly longer PFS (HR: 0.84 [0.74; 0.984], p = .0295). No significant differences were observed for changes of physical activity behavior. Patients who reported to be “active” at baseline revealed significantly fewer AEs compared to “insufficiently” active patients. In detail, both severe and non-severe AEs occurred less frequently in the “active” patients group. In line with that, QoL and fatigue were better in physical “active” patients compared to their insufficient active counterparts at the last post-baseline assessment. Participants who remained or become active indicated less AEs, a higher QoL, and reduced fatigue levels. Conclusions Physical activity behavior prior to medical treatment might have prognostic value in patients with advanced breast cancer in terms of extending the PFS. Moreover, physical activity before and during treatment may reduce treatment-related side effects and improve patients’ QoL and fatigue. Trial registration EUPAS9462. Registered 30th October 2012 “retrospectively registered.”

Abstract Acquisition of specialized cellular features is controlled by the ordered expression of transcription factors (TFs) along differentiation trajectories. Here, we find a member of the Onecut TF family, ONECUT3, expressed in postmitotic neurons that leave their Ascl1 +/Onecut1/2 + proliferative domain in the vertebrate hypothalamus to instruct neuronal differentiation. We combined single-cell RNA-seq and gain-of-function experiments for gene network reconstruction to show that ONECUT3 affects the polarization and morphogenesis of both hypothalamic GABA-derived dopamine and thyrotropin-releasing hormone (TRH)+ glutamate neurons through neuron navigator-2 (NAV2). In vivo, siRNA-mediated knockdown of ONECUT3 in neonatal mice reduced NAV2 mRNA, as well as neurite complexity in Onecut3-containing neurons, while genetic deletion of Onecut3/ceh-48 in C. elegans impaired neurocircuit wiring, and sensory discrimination-based behaviors. Thus, ONECUT3, conserved across neuronal subtypes and many species, underpins the polarization and morphological plasticity of phenotypically distinct neurons that descend from a common pool of Ascl1 + progenitors in the hypothalamus.

Abstract Background Emotional disorders such as depression and anxiety disorders share substantial similarities in their etiology and treatment. In recent decades, these commonalities have been increasingly recognized in classification systems and treatment programs crossing diagnostic boundaries. Methods To examine the prospective effects of different transdiagnostic markers on relevant treatment outcomes, we plan to track a minimum of N = 200 patients with emotional disorders during their routine course of cognitive behavioral therapy at two German outpatient clinics. We will collect a wide range of transdiagnostic markers, ranging from basic perceptual processes and self-report measures to complex behavioral and neurobiological indicators, before entering therapy. Symptoms and psychopathological processes will be recorded before entering therapy, between the 20th and 24th therapy session, and at the end of therapy. Discussion Our results could help to identify transdiagnostic markers with high predictive power, but also provide deeper insights into which patient groups with which symptom clusters are less likely to benefit from therapy, and for what reasons. Trial Registration The trial was preregistered at the German Clinical Trial Register (DRKS-ID: DRKS00031206; 2023–05-09).

Hydrothermal alteration and mineralization processes can affect the physical and chemical properties of volcanic rocks. Aggressive acidic degassing and fluid flow often also lead to changes in the appearance of a rock, such as changes in surface coloration or intense bleaching. Although hydrothermal alteration can have far-reaching consequences for rock stability and permeability, limited knowledge exists on the detailed structures, extent, and dynamic changes that take place near the surface of hydrothermal venting systems. By integrating drone-based photogrammetry with mineralogical and chemical analyses of rock samples and surface gas flux, we investigate the structure of the evolving volcanic degassing and alteration system at the La Fossa cone on the island of Vulcano, Italy. Our image analysis combines principal component analysis (PCA) with image classification and thermal analysis through which we identify an area of approximately 70 000 m2 that outlines the maximum extent of hydrothermal alteration effects at the surface, represented by a shift in rock color from reddish to gray. Within this area, we identify distinct gradients of surface coloration and temperature that indicate a local variability in the degassing and alteration intensity and define several structural units within the fumarole field. At least seven such larger units of increased activity could be constrained. Through mineralogical and geochemical analysis of samples from the different alteration units, we define a relationship between surface appearance in drone imagery and the mineralogical and chemical composition. Gradients in surface color from reddish to gray correlate with a reduction in Fe2O3 from up to 3.2 % in the unaltered regime to 0.3 % in the altered regime, and the latter coincides with the area of increased diffuse acid gas flux. As the pixel brightness increases towards higher alteration gradients, we note a loss of the initial (igneous) mineral fraction and a change in the bulk chemical composition with a concomitant increase in sulfur content from close to 0 % in the unaltered samples to up to 60 % in samples from the altered domains. Using this approach of combined remote-sensing and in situ analyses, we define and spatially constrain several alteration units and compare them to the present-day thermally active surface and degassing pattern over the main crater area. The combined results permit us to present a detailed anatomy of the La Fossa fumarole field, including high-temperature fumaroles and seven larger units of increased alteration intensity, surface temperature, and variably intense surface degassing. Importantly, we also identify apparently sealed surface domains that prevent degassing, likely as a consequence of mineral precipitation from degassing and alteration processes. By assessing the thermal energy release of the identified spatial units quantitatively, we show that thermal radiation of high-temperature fumaroles accounts for < 50 % of the total thermal energy release only and that the larger part is emitted by diffuse degassing units. The integrated use of methods presented here has proven to be a useful combination for a detailed characterization of alteration and activity patterns of volcanic degassing sites and has the potential for application in alteration research and for the monitoring of volcanic degassing systems.

Abstract Purpose A significant percentage of women experience psychopathological symptoms during the postpartum period, which can impact not only their mental health and well-being but also the relationship between mother and baby. However, studies investigating how specific psychological factors, such as self-compassion and self-criticism, contribute to the development and maintenance of these symptoms are scarce. Methods This cross-sectional study aimed to examine the relationship among compassionate self-responding (CSR), uncompassionate self-responding (USR), maternal mental health indicators, mother-infant bonding, and the perceived impact of the COVID-19 pandemic. Data were collected online from 189 Brazilian women with infants aged 0 to 12 months. Participants completed measures of sociodemographic characteristics, Self-Compassion Scale (SCS), Edinburgh Postnatal Depression Scale (EPDS), Postpartum Specific Anxiety Scale (PSAS-BR-RSF-C), Postpartum Bonding Questionnaire (PBQ), and COVID-19–Impact on Quality of Life (COV19-QoL). Results Through network analysis, our findings highlighted that postpartum depression played a central role in the structuring of variables in this system. Furthermore, USR, instead of CSR, emerged as the variable most strongly associated with levels of postpartum depression, which, in turn, was associated with mother-infant bonding. Conclusion Mitigating levels of self-criticism in mothers may represent a pathway to prevent the development of postpartum depression, which, in turn, could impact the quality of the mother-infant relationship. Given the significance of the child’s early years for their emotional development, intervening early in maternal mental health may be a means to prevent mental disorders in the child as well.

Abstract Phosphoethanolamine (pEtN) cellulose is a naturally occurring modified cellulose produced by several Enterobacteriaceae. The minimal components of the E. coli cellulose synthase complex include the catalytically active BcsA enzyme, a hexameric semicircle of the periplasmic BcsB protein, and the outer membrane (OM)-integrated BcsC subunit containing periplasmic tetratricopeptide repeats (TPR). Additional subunits include BcsG, a membrane-anchored periplasmic pEtN transferase associated with BcsA, and BcsZ, a periplasmic cellulase of unknown biological function. While cellulose synthesis and translocation by BcsA are well described, little is known about its pEtN modification and translocation across the cell envelope. We show that the N-terminal cytosolic domain of BcsA positions three BcsG copies near the nascent cellulose polymer. Further, the semicircle’s terminal BcsB subunit tethers the N-terminus of a single BcsC protein in a trans-envelope secretion system. BcsC’s TPR motifs bind a putative cello-oligosaccharide near the entrance to its OM pore. Additionally, we show that only the hydrolytic activity of BcsZ but not the subunit itself is necessary for cellulose secretion, suggesting a secretion mechanism based on enzymatic removal of translocation incompetent cellulose. Lastly, protein engineering introduces cellulose pEtN modification in orthogonal cellulose biosynthetic systems. These findings advance our understanding of pEtN cellulose modification and secretion.

Photosynthesis is initiated when the sun’s light induces electron transfer from chlorophyll to plastoquinone, a para-quinone. While photosynthesis occurs in the intact chloroplasts of living plants, similar photochemical reactions between dietary chlorophyll metabolites and quinones are likely and may affect health outcomes. Herein, we continue our studies of the direct photoreduction of para-quinones and ortho-quinones that were generated by the photo-oxidation of catechols. Chlorophyll metabolites, including pheophorbide A, chlorin e6, and pyropheophorbide A, as well as methylene blue were employed as photosensitizers. We detected hydrogen peroxide using horseradish peroxidase following the photo-oxidation of the catechol dopamine, even in the presence of EDTA, a tertiary amine electron donor. Under ambient oxygen, hydrogen peroxide was also detected after the photoreduction of several para-quinones, including 2,3-dimethoxy-5-methyl-p-benzoquinone (CoQ0), methoxy-benzoquinone, and methyl-benzoquinone. The combinations of methylene blue and EDTA or pheophorbide A and triethanolamine as the electron donor in 20% dimethylformamide were optimized for photoreduction of the para-quinones. Chlorin e6 and pyropheophorbide A were less effective for the photoreduction of CoQ0 but were equivalent to pheophorbide A for generating hydrogen peroxide in photo-oxidation reactions with photosensitizers, oxygen, and triethanolamine. We employed dinitrophenylhydrazine to generate intensely colored adducts of methoxy-benzoquinone, methyl-benzoquinone, and 1,4-benzoquinone.

Abstract The geological formation of the Muschelkalk is widespread in the center of the North German Basin (NGB) and is increasingly attracting interest for application of geothermal energy extraction or high-temperature aquifer thermal energy storage (HT-ATES). This study investigates the Middle Triassic “Rüdersdorfer Schaumkalk”, which was the former injection horizon of the natural gas storage facility in Berlin, Germany. For the first time, detailed chemical and microbiological analyses of formation water of this Lower Muschelkalk limestone formation were conducted and hydrogeochemically characterized. In addition, a hydrogeochemical model was developed to quantify the potential reactions during HT-ATES focusing on calcite dissolution and precipitation. The main objectives of this study are: (1) to determine the origin of the water from the three wells targeting the Muschelkalk aquifer, (2) to understand changes in hydrochemistry after system operation, and (3) to evaluate the long-term sustainability of a potential HT-ATES system with increasing temperature. The target formation is encountered by several wells at about 525 m below the surface with an average thickness of 30 m. Two hydraulic lifting tests including physical, chemical, and microbial groundwater as well as gas monitoring were carried out. In addition, several downhole samples of formation fluid were collected from the aquifer at in situ pressure and temperature conditions. Fluid analysis of the saline formation water indicate a seawater origin within the Muschelkalk with subsequent evaporation and various water–rock interactions with anhydrite/gypsum, dolomite, and calcite. With a salinity of 130 g/L, dominated by Na–Cl, a slightly acidic pH between 6 and 7, and a low gas content of 3%, the formation water fits to other saline deep formation waters of the NGB. Gas concentrations and microbial communities like sulfate-reducing bacteria and methanogenic archaea in the produced water indicate several geochemical alterations and microbial processes like corrosion and the forming of biogenic methane. Geochemical simulations of calcite equilibrium over 10 HT-ATES cycles indicated a pronounced propensity for calcite precipitation up to 31 mg/kgw, within the heat exchanger. At the same time, these models predicted a significant potential for calcite dissolution, with rates up to 21 mg/kgw, in both the cold and hot reservoirs. The results from the carbonate aquifer characterized in this study can be transferred to other sites in the NGB affected by salt tectonics and have provided information on the microbiological-chemical processes to be expected during the initial use of old wells.

Abstract Background Endovascular therapy for acute ischemic stroke has been shown to be highly effective in selected patients. However, the ideal criteria for patient selection are still debated. It is well known that collateral flow is an important factor, but the assessment is often subjective and time-consuming. Relative cerebral blood volume (rCBV) is a putative indicator of collateral capacity and can be quickly and easily determined by automated quantitative analysis. We investigated the relationship between rCBV of the affected region and clinical outcome in patients with acute ischemic stroke after endovascular therapy. Methods We conducted a retrospective study on consecutive patients between January 2017 and May 2019. Patients with acute ischemic stroke of the anterior circulation who underwent imaging including computed tomography perfusion and were treated with mechanical thrombectomy (MT) were eligible for inclusion. rCBV was calculated automatically with RAPID software by dividing the average cerebral blood volume (CBV) of the affected region (time-to-maximum (Tmax) > 6 s) by the CBV of the unaffected contralateral side. The primary outcome was determined by the modified Rankin Scale (mRS) after 90 days. Good clinical outcome was defined as mRS ≤ 2. We compared means, performed mono- and multivariate logistical regression and calculated a receiver operating characteristic (ROC)-analysis to determine the ideal cutoff value to predict clinical outcomes. Results 155 patients were enrolled in this study. 66 patients (42.58%) had good clinical outcomes. Higher rCBV was associated with good clinical outcome (p

Abstract Background To investigate the reproducibility of automated volumetric bone mineral density (vBMD) measurements from routine thoracoabdominal computed tomography (CT) assessed with segmentations by a convolutional neural network and automated correction of contrast phases, on diverse scanners, with scanner-specific asynchronous or scanner-agnostic calibrations. Methods We obtained 679 observations from 278 CT scans in 121 patients (77 males, 63.6%) studied from 04/2019 to 06/2020. Observations consisted of two vBMD measurements from Δdifferent reconstruction kernels (n = 169), Δcontrast phases (n = 133), scan Δsessions (n = 123), Δscanners (n = 63), or Δall of the aforementioned (n = 20), and observations lacking scanner-specific calibration (n = 171). Precision was assessed using root-mean-square error (RMSE) and root-mean-square coefficient of variation (RMSCV). Cross-measurement agreement was assessed using Bland-Altman plots; outliers within 95% confidence interval of the limits of agreement were reviewed. Results Repeated measurements from Δdifferent reconstruction kernels were highly precise (RMSE 3.0 mg/cm3; RMSCV 1.3%), even for consecutive scans with different Δcontrast phases (RMSCV 2.9%). Measurements from different Δscan sessions or Δscanners showed decreased precision (RMSCV 4.7% and 4.9%, respectively). Plot-review identified 12 outliers from different scan Δsessions, with signs of hydropic decompensation. Observations with Δall differences showed decreased precision compared to those lacking scanner-specific calibration (RMSCV 5.9 and 3.7, respectively). Conclusion Automatic vBMD assessment from routine CT is precise across varying setups, when calibrated appropriately. Low precision was found in patients with signs of new or worsening hydropic decompensation, what should be considered an exclusion criterion for both opportunistic and dedicated quantitative CT. Relevance statement Automated CT-based vBMD measurements are precise in various scenarios, including cross-session and cross-scanner settings, and may therefore facilitate opportunistic screening for osteoporosis and surveillance of BMD in patients undergoing routine clinical CT scans. Key Points Artificial intelligence-based tools facilitate BMD measurements in routine clinical CT datasets. Automated BMD measurements are highly reproducible in various settings. Reliable, automated opportunistic osteoporosis diagnostics allow for large-scale application. Graphical Abstract

Computational models of gene regulations help to understand regulatory mechanisms and are extensively used in a wide range of areas, e.g., biotechnology or medicine, with significant benefits. Unfortunately, there are only a few computational gene regulatory models of whole genomes allowing static and dynamic analysis due to the lack of sophisticated tools for their reconstruction. Here, we describe Augusta, an open-source Python package for Gene Regulatory Network (GRN) and Boolean Network (BN) inference from the high-throughput gene expression data. Augusta can reconstruct genome-wide models suitable for static and dynamic analyses. Augusta uses a unique approach where the first estimation of a GRN inferred from expression data is further refined by predicting transcription factor binding motifs in promoters of regulated genes and by incorporating verified interactions obtained from databases. Moreover, a refined GRN is transformed into a draft BN by searching in the curated model database and setting logical rules to incoming edges of target genes, which can be further manually edited as the model is provided in the SBML file format. The approach is applicable even if information about the organism under study is not available in the databases, which is typically the case for non-model organisms including most microbes. Augusta can be operated from the command line and, thus, is easy to use for automated prediction of models for various genomes. The Augusta package is freely available at github.com/JanaMus/Augusta. Documentation and tutorials are available at augusta.readthedocs.io.

Abstract Swine influenza A viruses (swIAV) cause an economically important respiratory disease in modern pig production. Continuous virus transmission and antigenic drift are difficult to control in enzootically infected pig herds. Here, antibody-positive piglets from a herd enzootically infected with swIAV H1N2 (clade 1 A.3.3.2) were immunized using a homologous prime-boost vaccination strategy with novel live attenuated influenza virus (LAIV) based on a reassortment-incompetent bat influenza-swIAV chimera or a vesicular stomatitis virus-based replicon vaccine. Challenge infection of vaccinated piglets by exposure to H1N2 swIAV-infected unvaccinated seeder pigs showed that both LAIV and replicon vaccine markedly reduced virus replication in the upper and lower respiratory tract, respectively, compared to piglets immunized with commercial heterologous or autologous adjuvanted whole-inactivated virus vaccines. Our novel vaccines may aid in interrupting continuous IAV transmission chains in large enzootically infected pig herds, improve the health status of the animals, and reduce the risk of zoonotic swIAV transmission.

Abstract Background Liver grafts are frequently declined due to high donor age or age mismatch with the recipient. To improve the outcome of marginal grafts, we aimed to characterize the performance of elderly vs. young liver grafts in a standardized rat model of normothermic ex vivo liver machine perfusion (NMP). Methods Livers from Sprague–Dawley rats aged 3 or 12 months were procured and perfused for 6 h using a rat NMP system or collected as a reference group (n = 6/group). Tissue, bile, and perfusate samples were used for biochemical, and proteomic analyses. Results All livers cleared lactate during perfusion and continued to produce bile after 6 h of perfusion (614 mg/h). Peak urea levels in 12-month-old animals were higher than in younger animals. Arterial and portal venous pressure, bile production and pH did not differ between groups. Proteomic analysis identified a total of 1477 proteins with oxidoreductase and catalytic activity dominating the gene ontology analysis. Proteins such as aldehyde dehydrogenase 1A1 and 2-Hydroxyacid oxidase 2 were significantly more present in livers of older age. Conclusions Young and elderly liver grafts exhibited similar viability during NMP, though proteomic analyses indicated that older grafts are less resilient to oxidative stress. Our study is limited by the elderly animal age, which corresponds to mature but not elderly human age typically seen in marginal human livers. Nevertheless, reducing oxidative stress could be a promising therapeutic target in the future.

Abstract Introduction : Amelogenesis imperfecta (AI) is a genetically determined, non-syndromic enamel dysplasia that may manifest as hypoplasia, hypomaturation, or hypocalcification and can commonly be classified into four primary groups. In this retrospective analysis, specific orofacial characteristics are described and associated with each of the AI types based on a patient cohort from Witten/Herdecke University, Germany. Methods Data from 19 patients (ten male and nine female, mean age 12.27 ± 4.06 years) with AI who presented at the Department of Orthodontics between July 2011 and December 2023 were analyzed. Baseline skeletal and dental conditions were assessed, including the presence of hypodontia, displacements, and taurodontism. AI was classified into classes I–IV based on phenotype. Treatment needs were evaluated according to the main findings following the German KIG classification, while the radiological enamel situation was determined using panoramic radiographs. Results An approximately equal distribution between classes II and III was found and a slight inclination toward a dolichofacial configuration (ΔML-NSL: 5.07 ± 9.23°, ΔML-NL: 4.24 ± 8.04°). Regarding orthodontic findings, disturbance in tooth eruption as well as open bite were the most prevalent issues (both 36.8%, n = 7). The most common AI classes were type I and II, which show an almost even distribution about the skeletal classes in sagittal dimension, while dolichofacial configuration was found most frequently in vertical dimension. Conclusion Both clinical and radiological orthodontic findings in context with AI are subject to extensive distribution. It seems that no specific orofacial findings can be confirmed in association with AI with regard to the common simple classes I–IV. It may be more appropriate to differentiate the many subtypes according to their genetic aspects to identify possible associated orthodontic findings.

Abstract Due to their exceptional solubility and stability, nanobodies have emerged as powerful building blocks for research tools and therapeutics. However, their generation in llamas is cumbersome and costly. Here, by inserting an engineered llama immunoglobulin heavy chain (IgH) locus into IgH-deficient mice, we generate a transgenic mouse line, which we refer to as ‘LamaMouse’. We demonstrate that LamaMice solely express llama IgH molecules without association to Igκ or λ light chains. Immunization of LamaMice with AAV8, the receptor-binding domain of the SARS-CoV-2 spike protein, IgE, IgG2c, and CLEC9A enabled us to readily select respective target-specific nanobodies using classical hybridoma and phage display technologies, single B cell screening, and direct cloning of the nanobody-repertoire into a mammalian expression vector. Our work shows that the LamaMouse represents a flexible and broadly applicable platform for a facilitated selection of target-specific nanobodies.

Abstract Despite substantial evidence emphasizing the pleiotropic benefits of exercise for the prevention and treatment of various diseases, the underlying biological mechanisms have not been fully elucidated. Several exercise benefits have been attributed to signaling molecules that are released in response to exercise by different tissues such as skeletal muscle, cardiac muscle, adipose, and liver tissue. These signaling molecules, which are collectively termed exerkines, form a heterogenous group of bioactive substances, mediating inter-organ crosstalk as well as structural and functional tissue adaption. Numerous scientific endeavors have focused on identifying and characterizing new biological mediators with such properties. Additionally, some investigations have focused on the molecular targets of exerkines and the cellular signaling cascades that trigger adaption processes. A detailed understanding of the tissue-specific downstream effects of exerkines is crucial to harness the health-related benefits mediated by exercise and improve targeted exercise programs in health and disease. Herein, we review the current in vivo evidence on exerkine-induced signal transduction across multiple target tissues and highlight the preventive and therapeutic value of exerkine signaling in various diseases. By emphasizing different aspects of exerkine research, we provide a comprehensive overview of (i) the molecular underpinnings of exerkine secretion, (ii) the receptor-dependent and receptor-independent signaling cascades mediating tissue adaption, and (iii) the clinical implications of these mechanisms in disease prevention and treatment.

Abstract Background Angiosarcoma of the adrenal gland is a very rare malignant vascular neoplasm. The clinical symptoms are atypical or completely absent. Angiosarcomas of the adrenal gland are therefore often discovered incidentally, and the diagnosis is made histologically after resection. Case presentation A 46-year-old white Spanish male who was a previous smoker and nondrinker and was slightly overweight (92 kg, 176 cm, body mass index 29.7 kg/m2) with no relevant medical history presented to the internal medicine emergency department of our hospital with an unclear 12 cm tumor of the right adrenal gland. Prior to the computed tomography scan, he had had persistent evening fevers for 4 months and unintentional weight loss of 5 kg. The laboratory results showed anemia and an elevated C-reactive protein, but no hormone production. We performed an open adrenalectomy of the right adrenal gland. Finally, the histologic findings revealed an angiosarcoma of the adrenal gland. Conclusion Even though angiosarcomas of the adrenal gland are rare, the differential diagnosis of an angiosarcoma should be considered if a malignant tumor of the adrenal gland is suspected. Treatment decisions should be made on an interdisciplinary basis and preferably in a specialized center. Owing to the rarity of angiosarcomas of the adrenal gland, it is necessary to continue to share clinical experience to gain a better understanding of this particular tumor entity.

Abstract In case of an emergency, health insurance in Germany provides easy access to medical care in emergency departments. Over 100,000 people do not have health insurance for various reasons. They are repeatedly refused treatment in emergency rooms as their right to care outside of regular insurance is often unknown or ignored.

Background: B cells represent a crucial component of adaptive immunity that ensures long-term protection from infection by generating pathogen-specific immunoglobulins. Exercise alters B cell counts and immunoglobulin levels, but evidence-based conclusions on potential benefits for adaptive immunity are lacking. This systematic review assessed current literatures on the impact of acute exercise and exercise training on B cells, immunoglobulins, and markers of secretory immunity in human biofluids. Methods: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, MEDLINE, Web of Science, and Embase were searched on March 8, 2023. Non-randomized controlled trials and crossover trials investigating the impact of acute exercise or exercise training on B cell counts and proportions, immunoglobulin levels, salivary flow rate, or secretory immunoglobulin A secretion rate were included. Quality and reporting of exercise training studies were assessed using the Tool for the Assessment of Study Quality and reporting in Exercise. Study characteristics, outcome measures, and statistically significant changes were summarized tabularly. Results: Of the 67 eligible studies, 22 applied acute exercise and 45 applied exercise training. All included outcomes revealed significant alterations over time in acute exercise and exercise training context, but only a few investigations showed significant differences compared to control conditions. Secretory and plasma immunoglobulin A levels were most consistently increased in response to exercise training. Conclusion: B cell-related outcomes are altered by acute exercise and exercise training, but evidence-based conclusions cannot be drawn with high confidence due to the large heterogeneity in populations and exercise modalities. Well-designed trials with large sample sizes are needed to clarify how exercise shapes B cell-related immunity.

Summary: Biomarkers have been instrumental in population selection and disease monitoring in clinical trials of recently FDA-approved drugs targeting amyloid-β to slow the progression of Alzheimer's disease (AD). As new therapeutic strategies and biomarker techniques emerge, the importance of biomarkers in drug development is growing exponentially. In this emerging landscape, biomarkers are expected to serve a wide range of contexts of use in clinical trials focusing on AD and related dementias. The joint FDA-NIH BEST (Biomarkers, EndpointS, and other Tools) framework provides standardised terminology to facilitate communication among stakeholders in this increasingly complex field. This review explores various applications of biomarkers relevant to AD clinical trials, using the BEST resource as a reference. For simplicity, we predominantly provide contextual characterizations of biomarkers use from the perspective of drugs targeting amyloid-β and tau proteins. However, general definitions and concepts can be extrapolated to other targets.

BackgroundPemphigus vulgaris (PV) is a life-threatening autoimmune blistering disease caused mainly by IgG autoantibodies (auto-abs) against the cadherin-type adhesion molecules desmoglein (Dsg) 1 and 3. Pathogenic anti-Dsg3 auto-abs bind to different Dsg3 epitopes, leading, among others, to signalling that is involved in pathogenic events, such as Dsg3 depletion. As central tools in research on PV, a limited number of antibodies such as AK23 are frequently used by the autoimmune bullous disease community.MethodsPreviously, we have introduced a novel Dsg3 EC5-binding antibody termed 2G4 that may potentially serve as a superior tool for numerous PV related analysis. The purpose of this study was to develop a quality-controlled production and verification process that allows I) a continuous quality improvement, and II) a verified and comprehensible overall quality with regard to pathogenic antigen-specific binding in a variety of pemphigus assays for each batch production.ResultsThus, a workflow based on a standardized operating procedure was established. This includes the verification of purity and in-vitro binding capacity (SDS-page, direct and indirect immunofluorescence) as primary parameters, and size analysis by mass-spectrometry and ex-vivo pathogenicity by monolayer dissociation assay.ConclusionWe here present an extensive point-by-point quality controlled IgG production protocol, which will serve as a basis for a standardized antibody assessment in PV research.

Background The acquisition of contrast‐enhanced T1 maps to calculate extracellular volume (ECV) requires contrast agent administration and is time consuming. This study investigates generative adversarial networks for contrast‐free, virtual extracellular volume (vECV) by generating virtual contrast‐enhanced T1 maps. Methods and Results This retrospective study includes 2518 registered native and contrast‐enhanced T1 maps from 1000 patients who underwent cardiovascular magnetic resonance at 1.5 Tesla. Recent hematocrit values of 123 patients (hold‐out test) and 96 patients from a different institution (external evaluation) allowed for calculation of conventional ECV. A generative adversarial network was trained to generate virtual contrast‐enhanced T1 maps from native T1 maps for vECV creation. Mean and SD of the difference per patient (ΔECV) were calculated and compared by permutation of the 2‐sided t test with 10 000 resamples. For ECV and vECV, differences in area under the receiver operating characteristic curve (AUC) for discriminating hold‐out test patients with normal cardiovascular magnetic resonance versus myocarditis or amyloidosis were tested with Delong's test. ECV and vECV showed a high agreement in patients with myocarditis (ΔECV: hold‐out test, 2.0%±1.5%; external evaluation, 1.9%±1.7%) and normal cardiovascular magnetic resonance (ΔECV: hold‐out test, 1.9%±1.4%; external evaluation, 1.5%±1.2%), but variations in amyloidosis were higher (ΔECV: hold‐out test, 6.2%±6.0%; external evaluation, 15.5%±6.4%). In the hold‐out test, ECV and vECV had a comparable AUC for the diagnosis of myocarditis (ECV AUC, 0.77 versus vECV AUC, 0.76; P=0.76) and amyloidosis (ECV AUC, 0.99 versus vECV AUC, 0.96; P=0.52). Conclusions Generation of vECV on the basis of native T1 maps is feasible. Multicenter training data are required to further enhance generalizability of vECV in amyloidosis.

Qualitative research is important to advance health equity as it offers nuanced insights into structural determinants of health inequities, amplifies the voices of communities directly affected by health inequities, and informs community-based interventions. The scale and frequency of public health crises have accelerated in recent years (e.g., pandemic, environmental disasters, climate change). The field of public health research and practice would benefit from timely and time-sensitive qualitative inquiries for which a practical approach to qualitative data analysis (QDA) is needed. One useful QDA approach stemming from sociology is flexible coding. We discuss our practical experience with a team-based approach using flexible coding for qualitative data analysis in public health, illustrating how this process can be applied to address multiple research questions simultaneously or asynchronously. We share lessons from this case study, while acknowledging that flexible coding has broader applicability across disciplines. Flexible coding provides an approachable step-by-step process that enables collaboration among coders of varying levels of experience to analyze large datasets. It also serves as a valuable training tool for novice coders, something urgently needed in public health. The structuring enabled through flexible coding allows for prioritizing urgent research questions, while preparing large datasets to be revisited many times, facilitating secondary analysis. We further discuss the benefit of flexible coding for increasing the reliability of results through active engagement with the data and the production of multiple analytical outputs.

Pattern transfer by plasma etching is a traditional standard technology in microelectronics and other micron technologies. These technologies require vacuum conditions, which limit throughput, size, and low-cost fabrication. Recent developments in low cost atmospheric plasma technologies may be suitable to realize pattern transfer without vacuum conditions. Reactive atmospheric plasma jet etching has been used to transfer aluminum mask patterns to fused silica. Aluminum line patterns of 2.5 to 50 µm width on fused silica wafer are exposed to a static as well as a scanning CF4/O2 reactive atmospheric plasma jet with a footprint diameter of 0.85 mm (full width at half maximum), resulting in etching only the SiO2 and causing a nearly isotropic etch with an etch rate of about 200 nm/s. As a result, line narrowing, trapezoidal line cross-sections, and under-etching were observed. The successfully transferred line patterns with the demonstrated widths and depths are of technological interest in various fields of application. Therefore, this approach enables low-cost patterning of fused silica through the use of reactive atmospheric plasma jet etching for micron-scale pattern transfer. This advancement addresses the limitations of both traditional vacuum-based and wet etching methods.

Summary: Isolating high-quality different cell types is a powerful approach for understanding cellular compositions and features in the heart, but it is challenging. The available protocols typically focus on isolating one or two cell types. Here, we present a protocol to simultaneously isolate high-quality and high-quantity cardiomyocytes and non-myocyte cells, including immune cells, from adult rat hearts. We describe steps for purifying cells using bovine serum albumin. We also detail procedures for viability analysis and cell type identification using fluorescence-activated cell sorting.For complete details on the use and execution of this protocol, please refer to Zhang et al.,1 Valkov et al.,2 Vang et al.,3 and Li et al.4 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Objective: to describe factors of influence of telenursing on naturalistic decision making about self-care of people with heart failure during COVID-19. Method: this is a descriptive study with a qualitative approach, with 16 participants interviewed after hospitalization for decompensated heart failure. The data was collected using audio and video technology and submitted to content analysis, guided by the Situation-Specific Theory of Heart Failure Self-Care. Result: two thematic categories emerged from the analysis: Self-care as a decision-making process and Factors influencing decision-making, which describe tele-nursing as a support resource for people with heart failure, during changes in care in the pandemic period. Conclusion: it was possible to understand the relationship between telenursing and the establishment of a bond, in order to stimulate naturalistic decision-making by people with heart failure in their daily lives in a coherent way, leading to better health outcomes.

Live-attenuated influenza vaccines (LAIV) offer advantages over the commonly used inactivated split influenza vaccines. However, finding the optimal balance between sufficient attenuation and immunogenicity has remained a challenge. We recently developed an alternative LAIV based on the 2009 pandemic H1N1 virus with a truncated NS1 protein and lacking PA-X protein expression (NS1(1-126)-ΔPAX). This virus showed a blunted replication and elicited a strong innate immune response. In the present study, we evaluated the efficacy of this vaccine candidate in the porcine animal model as a pertinent in vivo system. Immunization of pigs via the nasal route with the novel NS1(1-126)-ΔPAX LAIV did not cause disease and elicited a strong mucosal immune response that completely blocked replication of the homologous challenge virus in the respiratory tract. However, we observed prolonged shedding of our vaccine candidate from the upper respiratory tract. To improve LAIV safety, we developed a novel prime/boost vaccination strategy combining primary intramuscular immunization with a haemagglutinin-encoding propagation-defective vesicular stomatitis virus (VSV) replicon, followed by a secondary immunization with the NS1(1-126)-ΔPAX LAIV via the nasal route. This two-step immunization procedure significantly reduced LAIV shedding, increased the production of specific serum IgG, neutralizing antibodies, and Th1 memory cells, and resulted in sterilizing immunity against homologous virus challenge. In conclusion, our novel intramuscular prime/intranasal boost regimen interferes with virus shedding and transmission, a feature that will help combat influenza epidemics and pandemics.

We report an index patient with complete insensitivity to pain and a history of painless fractures, joint hypermobility, and behavioral problems. The index patient descends from a family with notable cases among his maternal relatives, including his aunt and his mother’s first cousin, both of whom suffer from congenital insensitivity to pain. The patient had normal results for prior genetic testing: fragile-X syndrome testing, chromosomal microarray analysis, and exome sequencing. Optical genome mapping detected a homozygous deletion affecting the noncoding 5′ untranslated region (UTR) and the first non-coding exon of the SCN9A gene in all affected family members, compatible with recessive disease transmission. Pathogenic homozygous loss-of-function variants in the SCN9A gene are associated with impaired pain sensation in humans. Optical genome mapping can thus detect pathogenic structural variants in patients without molecular etiology by standard diagnostic procedures and is a more accessible diagnostic tool than short-read or long-read whole-genome sequencing.

Summary: Noxious stimuli activate nociceptive sensory neurons, causing action potential firing and the release of diverse signaling molecules. Several peptides have already been identified to be released by sensory neurons and shown to modulate inflammatory responses and inflammatory pain. However, it is still unclear whether lipid mediators can be released upon sensory neuron activation to modulate intercellular communication. Here, we analyzed the lipid secretome of capsaicin-stimulated nociceptive neurons with LC-HRMS, revealing that oleic acid is strongly released from sensory neurons by capsaicin. We further demonstrated that oleic acid inhibits capsaicin-induced calcium transients in sensory neurons and reverses bradykinin-induced TRPV1 sensitization by a calcineurin (CaN) and GPR40 (FFAR1) dependent pathway. Additionally, oleic acid alleviated zymosan-mediated thermal hypersensitivity via the GPR40, suggesting that the capsaicin-mediated oleic acid release from sensory neurons acts as a protective and feedback mechanism, preventing sensory neurons from nociceptive overstimulation via the GPR40/CaN/TRPV1-axis.

Lasting thalamus volume reduction after preterm birth is a prominent finding. However, whether thalamic nuclei volumes are affected differentially by preterm birth and whether nuclei aberrations are relevant for cognitive functioning remains unknown.Using T1-weighted MR-images of 83 adults born very preterm (≤ 32 weeks’ gestation; VP) and/or with very low body weight (≤ 1,500 g; VLBW) as well as of 92 full-term born (≥ 37 weeks’ gestation) controls, we compared thalamic nuclei volumes of six subregions (anterior, lateral, ventral, intralaminar, medial, and pulvinar) across groups at the age of 26 years. To characterize the functional relevance of volume aberrations, cognitive performance was assessed by full-scale intelligence quotient using the Wechsler Adult Intelligence Scale and linked to volume reductions using multiple linear regression analyses.Thalamic volumes were significantly lower across all examined nuclei in VP/VLBW adults compared to controls, suggesting an overall rather than focal impairment. Lower nuclei volumes were linked to higher intensity of neonatal treatment, indicating vulnerability to stress exposure after birth. Furthermore, we found that single results for lateral, medial, and pulvinar nuclei volumes were associated with full-scale intelligence quotient in preterm adults, albeit not surviving correction for multiple hypotheses testing.These findings provide evidence that lower thalamic volume in preterm adults is observable across all subregions rather than focused on single nuclei. Data suggest the same mechanisms of aberrant thalamus development across all nuclei after premature birth.

The growth pattern of oropharyngeal squamous cell carcinomas (OPSCC) varies from compact tumor cell aggregates to diffusely infiltrating tumor cell-clusters. The influence of the growth pattern on local tumor control and survival has been studied mainly for surgically treated oral cavity carcinomas on a visual basis. In this study, we used multiplex immunofluorescence staining (mIF) to examine the antigens pan-cytokeratin, p16INK4a, Ki67, CD271, PD-L1, and CD8 in pretherapeutic biopsies from 86 OPSCC. We introduce Tumor-stroma contact ratio (TSC), a novel parameter, to quantify the relationship between tumor cells in contact with the stromal surface and the total number of epithelial tumor cells. mIF tumor cores were analyzed at the single-cell level, and tumor-stromal contact area was quantified using the R package ''Spatstat''. TSC was correlated with the visually assessed invasion pattern by two independent investigators. Furthermore, TSC was analyzed in relation to clinical parameters and patient survival data to evaluate its potential prognostic significance.Higher TSC correlated with poor response to (chemo-)radiotherapy (r = 0.3, p < 0.01), and shorter overall (OS) and progression-free (PFS) survival (median OS: 13 vs 136 months, p < 0.0001; median PFS: 5 vs 85 months, p < 0.0001). Visual categorization of growth pattern according to established criteria of tumor aggressiveness showed interobserver variability increasing with more nuanced categories (2 categories: k = 0.7, 95 %-CI: 0.55 - 0.85; 4 categories k = 0.48, 95 %-CI: 0.35 - 0.61).In conclusion, TSC is an objective and reproducible computer-based parameter to quantify tumor-stroma contact area. We demonstrate its relevance for the response of oropharyngeal carcinomas to primary (chemo-)radiotherapy.

Abstract Background 1H-MRS is increasingly used in basic and clinical research to explain brain function and alterations respectively. In psychosis research it is now one of the main tools to investigate imbalances in the glutamatergic system. Interestingly, however, the findings are extremely variable even within patients of similar disease states. One reason may be the variability in analysis strategies, despite suggestions for standardization. Therefore, our study aimed to investigate the extent to which the basis set configuration– which metabolites are included in the basis set used for analysis– would affect the spectral fit and estimated glutamate (Glu) concentrations in the anterior cingulate cortex (ACC), and whether any changes in levels of glutamate would be associated with psychotic-like experiences and autistic traits. Methods To ensure comparability, we utilized five different exemplar basis sets, used in research, and two different analysis tools, r-based spant applying the ABfit method and Osprey using the LCModel. Results Our findings revealed that the types of metabolites included in the basis set significantly affected the glutamate concentration. We observed that three basis sets led to more consistent results across different concentration types (i.e., absolute Glu in mol/kg, Glx (glutamate + glutamine), Glu/tCr), spectral fit and quality measurements. Interestingly, all three basis sets included phosphocreatine. Importantly, our findings also revealed that glutamate levels were differently associated with both schizotypal and autistic traits depending on basis set configuration and analysis tool, with the same three basis sets showing more consistent results. Conclusions Our study highlights that scientific results may be significantly altered depending on the choices of metabolites included in the basis set, and with that emphasizes the importance of carefully selecting the configuration of the basis set to ensure accurate and consistent results, when using MR spectroscopy. Overall, our study points out the need for standardized analysis pipelines and reporting.

Abstract Background Nowadays, there is no method to quantitatively characterize the material composition of acute ischemic stroke thrombi prior to intervention, but dual-energy CT (DE-CT) offers imaging-based multimaterial decomposition. We retrospectively investigated the material composition of thrombi ex vivo using DE-CT with histological analysis as a reference. Methods Clots of 70 patients with acute ischemic stroke were extracted by mechanical thrombectomy and scanned ex vivo in formalin-filled tubes with DE-CT. Multimaterial decomposition in the three components, i.e., red blood cells (RBC), white blood cells (WBC), and fibrin/platelets (F/P), was performed and compared to histology (hematoxylin/eosin staining) as reference. Attenuation and effective Z values were assessed, and histological composition was compared to stroke etiology according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. Results Histological and imaging analysis showed the following correlation coefficients for RBC (r = 0.527, p

Abstract Right ventricular failure (RVF) after cardiac surgery is associated with an in-hospital mortality rate of up to 75%. Microaxial flow pumps are one of the mechanical circulatory supports (MCS) options available for the treatment of RVF, however the specifics of timing and indication for MCS, as well as predictors for survival, remain unclear due to a dearth of published data. We evaluated the clinical outcome of patients treated with Impella-RP for predictors of mortality and the hemodynamic effects of the pump. This is a single-center retrospective observational study involving adult patients who underwent cardiac surgery with cardiopulmonary bypass between January 2019 and December 2020 in cardiac surgery and required therapeutic management of RVF with an Impella-RP. Overall, 18 patients were included and analyzed for factors that could be associated with mortality, or that could be predictors of patient outcomes for this population. Treatment of RVF with Impella-RP improved the patient hemodynamics significantly and had a survival rate of 61% within 30 days. Patients with isolated CABG or better liver function before implantation had a better survival rate, which may indicate that underlying disease and timing of implantation are significant for successful treatment of RVF.

Wastewater-based epidemiology (WBE) is useful for detecting pathogen prevalence and may serve to effectively monitor diseases across broad scales. WBE has been used throughout the COVID-19 pandemic to track disease burden through quantifying SARS-CoV-2 RNA present in wastewater. Aside from case load estimation, WBE is being used to assay viral genomic diversity and emerging potential SARS-CoV-2 variants. Here, we present a study in which we sequenced RNA extracted from sewage influent obtained from eight wastewater treatment plants representing 16 million people in Southern California from April 2020 to August 2021. We sequenced SARS-CoV-2 with two methods: Illumina Respiratory Virus-Enriched metatranscriptomic sequencing (N = 269), and QIAseq SARS-CoV-2-tiled amplicon sequencing (N = 95). We classified SARS-CoV-2 reads into lineages and sublineages that approximated named variants and identified single nucleotide variants (SNVs), of which many are putatively novel SNVs and SNVs of unknown potential function and prevalence. Through our retrospective study, we also show that several SARS-CoV-2 sublineages were detected in wastewater before clinical detection, which may assist in the prediction of future variants of concern. Lastly, we show that sublineage diversity was similar across Southern California and that diversity changed over time, indicating that WBE is effective across megaregions. As the COVID-19 pandemic moves to new phases, and SARS-CoV-2 variants emerge, monitoring wastewater is important to understand local- and population-level dynamics of the virus. These results will aid in our ability to monitor the evolutionary potential of SARS-CoV-2 and help understand circulating SNVs to further combat COVID-19.

Abstract Background Teamwork in emergency medical services is a very important factor in efforts to improve patient safety. The potential differences of staff gender on communication, patient safety, and teamwork were omitted. The aim of this study is to evaluate these inadequately examined areas. Methods A descriptive and anonymous study was conducted with an online questionnaire targeting emergency physicians and paramedics. The participants were asked about teamwork, communication, patient safety and handling of errors. Results Seven hundred fourteen prehospital professionals from all over Germany participated. A total of 65.7% of the women harmed a patient (men 72.9%), and 52.6% were ashamed when mistakes were made (men 31.7%). 19.0% of the female participants considered their communication skills to be very good, compared to 81% of the men. More women than men did not want to appear incompetent (28.4%, 15.5%) and therefore did not speak openly about mistakes. Both genders saw the character of their colleagues as a reason for poor team communication (women 89.4%, men 84.9.%). Under high stress, communication decreased (women 35.9%, men 31.0%) and expression became inaccurate (women 18.7%, men 20.1%). Conclusions Team communication problems and teamwork in rescue services are independent of gender. Women seem to have more difficulty with open communication about mistakes because they seem to be subject to higher expectations. Work organization should be adapted to women’s needs to enable more effective error management. We conclude that it is necessary to promote a positive error and communication culture to increase patient safety.

Abstract Blood-based biomarkers for screening may guide tau positrion emissition tomography (PET) scan referrals to optimize prognostic evaluation in Alzheimer’s disease. Plasma Aβ42/Aβ40, pTau181, pTau217, pTau231, NfL, and GFAP were measured along with tau-PET in memory clinic patients with subjective cognitive decline, mild cognitive impairment or dementia, in the Swedish BioFINDER-2 study (n = 548) and in the TRIAD study (n = 179). For each plasma biomarker, cutoffs were determined for 90%, 95%, or 97.5% sensitivity to detect tau-PET-positivity. We calculated the percentage of patients below the cutoffs (who would not undergo tau-PET; “saved scans”) and the tau-PET-positivity rate among participants above the cutoffs (who would undergo tau-PET; “positive predictive value”). Generally, plasma pTau217 performed best. At the 95% sensitivity cutoff in both cohorts, pTau217 resulted in avoiding nearly half tau-PET scans, with a tau-PET-positivity rate among those who would be referred for a scan around 70%. And although tau-PET was strongly associated with subsequent cognitive decline, in BioFINDER-2 it predicted cognitive decline only among individuals above the referral cutoff on plasma pTau217, supporting that this workflow could reduce prognostically uninformative tau-PET scans. In conclusion, plasma pTau217 may guide selection of patients for tau-PET, when accurate prognostic information is of clinical value.

The aim of this study was to determine whether adolescents’ emotional problems, coping flexibility, age, and stress appraisals account for ways of coping, which include engagement and disengagement coping, with academic-, parent-, and peer-related stressful events. Stress appraisals were defined as perceived threats to the psychological needs of relatedness, competence, and autonomy. Models were fit at a higher order level, indicated by adolescents’ appraisals and intended ways of coping with stress in three domains (i.e., academic, parent, and peer) and tested at the lower level within each domain. Adolescents (N = 410; age 10–15; Mage = 12.5; 50% girls) reported their emotional problems (combined depressive and anxiety symptoms) and coping flexibility six months prior to completing an analogue task. The task involved viewing six short film clips portraying stressful events (e.g., obtaining a worse than expected exam grade or arguing with a parent) and reporting three stress appraisals and eight ways of coping after each stressor. The ways of coping were analyzed as four composite scores reflecting engagement coping (active coping, self-reliance) or disengagement coping (withdrawal coping, helplessness). In structural equation models, adolescents who appraised more threat reported more withdrawal coping and helplessness but also more active coping and self-reliance. Adolescents with more emotional problems appraised more threat and anticipated using less constructive ways of coping, whereas adolescents higher in coping flexibility intended to use more constructive ways of coping, with these associations sufficiently modeled at the general (across stress domains) level. Improvement in the model fit was found when appraised threat–coping associations were modeled at the lower (specific stressor domain) level, suggesting differences by stressor domain. Age was associated with more self-reliance and helplessness, with self-reliance being specific to parent stressors and helplessness specific to peer stressors.

Abstract Coastal mountain rivers export disproportionately high quantities of terrestrial organic carbon (OC) directly to the ocean, feeding microbial communities and altering coastal ecology. To better predict and mitigate the effects of wildfires on aquatic ecosystems and resources, we must evaluate the relationships between fire, hydrology, and carbon export, particularly in the fire‐prone western United States. This study examined the spatiotemporal export of particulate and dissolved OC (POC and DOC, respectively) and particulate and dissolved black carbon (PBC and DBC, respectively) from five coastal mountain watersheds following the 2020 CZU Lightning Complex Fires (California, USA). Despite high variability in watershed burn extent (20–98%), annual POC, DOC, PBC, and DBC concentrations remained relatively stable among the different watersheds. Instead, they correlated significantly with watershed discharge. Our findings indicate that hydrology, rather than burn extent, is a primary driver of post‐fire carbon export in coastal mountain watersheds.

Background: We know relatively little about how healthcare personnel (HCP) in long-term care facilities (LTCFs) integrate hand hygiene (HH) and personal protective equipment (PPE; e.g., gloves) use into their care processes. To address this gap, we are examining HH and PPE adherence at critical and contaminating moments in LTCFs. Methods: We conducted ethnographic observations of HCP’s processes of care in 2 LTCFs in Iowa to examine HH and PPE adherence during contaminating tasks in resident care sequences. We captured care observations and additional data on topics related to our study focus (e.g., unit/room layouts, PPE storage, facility policies/procedures) in field notes. We transcribed and imported fieldnotes into MAXQDA qualitative data management software and analyzed the data using a combined deductive-inductive coding approach. Results: Between 1/2023-7/2023, we observed 60 (30 per facility) care episodes. Most observations included toileting activities and perineal care during which HCP would be expected to use gloves and/or do HH. Most HCP appropriately donned/doffed gloves and practiced HH at key moments (e.g., before clean/aseptic procedures, after perineal care), but were less compliant before/after touching residents’ clothing or bare skin during these activities. In addition, some held soiled items next to their scrubs between tasks, which could contaminate their clothing and arms and could facilitate transmission of pathogens to other residents. Moreover, HCP’s interactions with floors emerged inductively as a topic of interest during our observations and preliminary analyses. We observed HCP interact with the floor during these activities in ways that could increase risk of pathogen transmission. HCP frequently dropped soiled towels or wipes used in perineal care onto the floor during tasks for later pick up. HCP also moved or placed trash bags containing soiled or contaminated items on the floor. HCP routinely knelt on, sat on, or touched their hands on the same floor when talking with residents, helping residents change clothes or diapers, changing bedding, or adjusting wheelchair footpads. In one case, the HCP picked up clean towels that fell to the floor near soiled towels and then used the “clean towels” in resident perineal care. Conclusion: Despite practicing HH and appropriate PPE use, HCP in LTCFs may increase the risk of pathogen transmission unintentionally through their interactions with soiled items and the environment, including floors. Given the nature of resident care in LTCFs, HCP in LTCF may be more likely than HCP in acute care settings to interact with contaminated floors.

OBJECTIVES:. Cardiogenic shock (CS) is associated with high mortality. Patients treated for CS mostly require heparin therapy, which may be associated with complications such as heparin-induced thrombocytopenia (HIT). HIT represents a serious condition associated with platelet decline and increased hypercoagulability and remains a poorly researched field in intensive care medicine. Primary purpose of this study was to: 1) determine HIT prevalence in CS, 2) assess the performance of common diagnostic tests for the workup of HIT, and 3) compare outcomes in CS patients with excluded and confirmed HIT. DESIGN:. Retrospective dual-center study including adult patients 18 years old or older with diagnosed CS and suspected HIT from January 2010 to November 2022. SETTING:. Cardiac ICU at the Ludwig-Maximilians University hospital in Munich and the university hospital of Bonn. PATIENTS AND INTERVENTIONS:. In this retrospective analysis, adult patients with diagnosed CS and suspected HIT were included. Differences in baseline characteristics, mortality, neurologic and safety outcomes between patients with excluded and confirmed HIT were evaluated. MEASUREMENTS AND MAIN RESULTS:. In cases of suspected HIT, positive screening antibodies were detected in 159 of 2808 patients (5.7%). HIT was confirmed via positive functional assay in 57 of 2808 patients, corresponding to a prevalence rate of 2.0%. The positive predictive value for anti-platelet factor 4/heparin screening antibodies was 35.8%. Total in-hospital mortality (58.8% vs. 57.9%; p > 0.999), 1-month mortality (47.1% vs. 43.9%; p = 0.781), and 12-month mortality (58.8% vs. 59.6%; p > 0.999) were similar between patients with excluded and confirmed HIT, respectively. Furthermore, no significant difference in neurologic outcome among survivors was found between groups (Cerebral Performance Category [CPC] score 1: 8.8% vs. 8.8%; p > 0.999 and CPC 2: 7.8% vs. 12.3%; p = 0.485). CONCLUSIONS:. HIT was a rare complication in CS patients treated with unfractionated heparin and was not associated with increased mortality. Also, HIT confirmation was not associated with worse neurologic outcome in survivors. Future studies should aim at developing more precise, standardized, and cost-effective strategies to diagnose HIT and prevent complications.

AimsThis systematic review and meta-analysis aimed to assess the efficacy of NMDA antagonists in ASD (Autism Spectrum Disorder) on the core (communication and social interaction, repetitive behavior) and associated symptoms (irritability) of ASD, as well as their safety.MethodsPubMed, CENTRAL, CINHAL, EMBASE, and PsycINFO databases were searched until November 2023. Two authors independently selected the studies and extracted data. Randomized controlled trials assessing the efficacy of NMDA receptor antagonists in participants with ASD aged

Abstract The creation of fractures in bedrock dictates water movement through the critical zone, controlling weathering, vadose zone water storage, and groundwater recharge. However, quantifying connections between fracturing, water flow, and chemical weathering remains challenging because of limited access to the deep critical zone. Here we overcome this challenge by coupling measurements from borehole drilling, groundwater monitoring, and seismic refraction surveys in the central California Coast Range. Our results show that the subsurface is highly fractured, which may be driven by the regional geologic and tectonic setting. The pervasively fractured rock facilitates infiltration of meteoric water down to a water table that aligns with oxidation in exhumed rock cores and is coincident with the adjacent intermittent first‐order stream channel. This work highlights the need to incorporate deep water flow and weathering due to pervasive fracturing into models of catchment water balances and critical zone weathering, especially in tectonically active landscapes.

Amidst the COVID-19 pandemic, many universities shifted to fully online learning. This study contributes to the existing online learning literature by examining the connection between course success, student engagement, and levels of computer and computer-mediated communication anxiety. The research delves into understanding the impact of anxiety on course engagement and the relationship between engagement and overall course success. Regression analyses were used to test hypotheses, revealing an interaction between computer anxiety and computer-mediated communication anxiety. The study underscores the importance of student engagement with course materials, particularly for assignments that require higher-order thinking. In contrast, objective quizzes and tests that do not require higher-order thinking were unaffected by engagement. The findings emphasize the collective responsibility of professors, advisors, and universities to improve student engagement. Recommendations include structuring courses to address anxiety, employing gamification techniques for technical classes, and fostering connections through discussion boards in online courses. Increasing engagement emerges as a pivotal strategy for academic success.

IntroductionP2X receptors are a family of homo- and heterotrimeric cation channels gated by extracellular ATP. The P2X4 and P2X7 subunits show overlapping expression patterns and have been involved in similar physiological processes, such as pain and inflammation as well as various immune cell functions. While formation of P2X2/P2X3 heterotrimers produces a distinct pharmacological phenotype and has been well established, functional identification of a P2X4/P2X7 heteromer has been difficult and evidence for and against a physical association has been found. Most of this evidence stems, however, from in vitro model systems.MethodsHere, we used a P2X7-EGFP BAC transgenic mouse model as well as P2X4 and P2X7 knock-out mice to re-investigate a P2X4-P2X7 interaction in mouse lung by biochemical and immunohistochemical experiments as well as quantitative expression analysis.ResultsNo detectable amounts of P2X4 could be co-purified from mouse lung via P2X7-EGFP. In agreement with these findings, immuno-histochemical analysis using a P2X7-specific nanobody revealed only limited overlap in the cellular and subcellular localizations of P2X4 and P2X7 in both the native lung tissue and primary cells. Comparison of P2X4 and P2X7 transcript and protein levels in the respective gene-deficient and wild type mice showed no mutual interrelation between their expression levels in whole lungs. However, a significantly reduced P2rx7 expression was found in alveolar macrophages of P2rx4-/- mice.DiscussionIn summary, our detailed analysis of the cellular and subcellular P2X4 and P2X7 localization and expression does not support a physiologically relevant direct association of P2X4 and P2X7 subunits or receptors in vivo.

BackgroundImmune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%–46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management.MethodsPatients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases (n = 12) were analyzed by Nanostring and compared to healthy heart muscle (n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients (n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy (n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry.ResultsA total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and –if required–second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4–1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis.ConclusionInterestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.

BackgroundScreening for gene mutations has become routine clinical practice across numerous tumor entities, including melanoma. BAP1 gene mutations have been identified in various tumor types and acknowledged as a critical event in metastatic uveal melanoma, but their role in non-uveal melanoma remains inadequately characterized.MethodsA retrospective analysis of all melanomas sequenced in our department from 2014–2022 (n=2650) was conducted to identify BAP1 mutated samples. Assessment of clinical and genetic characteristics was performed as well as correlations with treatment outcome.ResultsBAP1 mutations were identified in 129 cases and distributed across the entire gene without any apparent hot spots. Inactivating BAP1 mutations were more prevalent in uveal (55%) compared to non-uveal (17%) melanomas. Non-uveal BAP1 mutated melanomas frequently exhibited UV-signature mutations and had a significantly higher mutation load than uveal melanomas. GNAQ and GNA11 mutations were common in uveal melanomas, while MAP-Kinase mutations were frequent in non-uveal melanomas with NF1, BRAF V600 and NRAS Q61 mutations occurring in decreasing frequency, consistent with a strong UV association. Survival outcomes did not differ among non-uveal melanoma patients based on whether they received targeted or immune checkpoint therapy, or if their tumors harbored inactivating BAP1 mutations.ConclusionIn contrast to uveal melanomas, where BAP1 mutations serve as a significant prognostic indicator of an unfavorable outcome, BAP1 mutations in non-uveal melanomas are primarily considered passenger mutations and do not appear to be relevant from a prognostic or therapeutic perspective.

ABSTRACT SARS-CoV-2 virus emerged as a new threat to humans and spread around the world, leaving a large death toll. As of January 2023, Brazil is among the countries with the highest number of registered deaths. Nonpharmacological and pharmacological interventions have been heterogeneously implemented in the country, which, associated with large socioeconomic differences between the country regions, has led to distinct virus spread dynamics. Here, we investigate the spatiotemporal dispersion of SARS-CoV-2 lineages in the Pernambuco state (Northeast Brazil) throughout the distinct epidemiological scenarios that unfolded in the first 2 years of the pandemic. We generated a total of 1,389 new SARS-CoV-2 genomes from June 2020 to August 2021. This sampling captured the arrival, communitary transmission, and the circulation of the B1.1, B.1.1.28, and B.1.1.33 lineages; the emergence of the former variant of interest P.2; and the emergence and fast replacement of all previous variants by the more transmissible variant of concern P.1 (Gamma). Based on the incidence and lineage spread pattern, we observed an East-to-West to inner state pattern of transmission, which is in agreement with the transmission of more populous metropolitan areas to medium- and small-size country-side cities in the state. Such transmission patterns may be partially explained by the main routes of traffic across municipalities in the state. Our results highlight that the fine-grained intrastate analysis of lineages and incidence spread can provide actionable insights for planning future nonpharmacological intervention for air-borne transmissible human pathogens.IMPORTANCEDuring the COVID-19 pandemic, Brazil was one of the most affected countries, mainly due its continental-size, socioeconomic differences among regions, and heterogeneous implementation of intervention methods. In order to investigate SARS-CoV-2 dynamics in the state of Pernambuco, we conducted a spatiotemporal dispersion study, covering the period from June 2020 to August 2021, to comprehend the dynamics of viral transmission during the first 2 years of the pandemic. Throughout this study, we were able to track three significant epidemiological waves of transmission caused by B1.1, B.1.1.28, B.1.1.33, P.2, and P.1 lineages. These analyses provided valuable insights into the evolution of the epidemiological landscape, contributing to a deeper understanding of the dynamics of virus transmission during the early years of the pandemic in the state of Pernambuco.

Introduction: The German Resuscitation Registry was started in 2007 and collects data on out-of-hospital as well as in-hospital cardiac arrest and resuscitation. It has collected more than 400.000 datasets till today. Methods: The German Resuscitation Registry (GRR) is a voluntary quality improvement tool and research tool for out-of-hospital and in-hospital resuscitation as well as in-hospital emergency treatment. It collects data for initial treatment, in-hospital care as well as long-term outcome in an online database. For risk stratification two scores have been developed, published, and implemented. The participants are getting annual and monthly or quarterly reports in addition to the standardized online, 24/7 available analyzing options. An annual public report is published as well. We are reporting on the OHCA annual report of 2022. Results: In 2022 the incidence of CPR started or continued by EMS was 77.6/100.000 inhabitants/year. The mean age was 70.2 years and 66.7% were male bystanders who started CPR in 51.3%. The average response time for the first EMS vehicle to arrive on scene was 6:55 min.In 57.9% of the cases, they had a presumed cardiac cause. The primary outcome, return-of-spontaneous circulation (ROSC) was achieved in 42.1%. Discussion: With its more than 450.000 included datasets, the GRR is an established tool for quality improvement and research in Germany and internationally. The results for the incidence of OHCA and outcome from 2022 are compared to EuReCa TWO data ranging in the upper third of European countries. Furthermore, the GRR has contributed to increasing knowledge of OHCA by conducting and publishing research e.g. on epidemiology, airway management, and medication of OHCA.