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The flexibility in growth of Betula pubescens is taken as example for possible erroneous imaginations of Late Glacial–Early Holocene living conditions. The article highlights the factors influencing the phenotype of the contemporary plants, as well as the small-scale patchiness of the distribution of the vegetation in the landscape. The area of investigation is the southern Weichselian younger morainic area of Schleswig-Holstein, including a major Late Glacial archaeological type locality – the Ahrensburg tunnel valley. The period under investigation spans the time between 11 700 and 11 400 cal BP and hence the Late Glacial–Early Holocene transition, which is characterized by a significant shift in the vegetation. This shift has often been seen as a simple transition from treeless tundra to birch forest. The aim of the article is to provide a more realistic image of plant cover of the late Dryas 3 period and the Early Holocene period before the Preboreal oscillation by considering past natural growth limits of Betula pubescens in the study area. The intention is to provide a more accessible interpretation of palaeobotanical data to non-specialists, especially in archaeology.

The optimisation of the power output of wind turbines requires the consideration of various aspects including turbine design, wind farm layout and more. An improved understanding of the interaction of wind turbines with the atmospheric boundary layer is an essential prerequisite for such optimisations. With numerical simulations, a variety of different situations and turbine designs can be compared and evaluated. For such a detailed analysis, the output of an extensive number of turbine and flow parameters is of great importance. In this paper a coupling of the aeroelastic code FAST (fatigue, aerodynamics, structures, and turbulence) and the large-eddy simulation tool PALM (parallelised large-eddy simulation model) is presented. The advantage of the coupling of these models is that it enables the analysis of the turbine behaviour, among others turbine power, blade and tower loads, under different atmospheric conditions. The proposed coupling is tested with the generic National Renewable Energy Laboratory (NREL) 5 MW turbine and the operational eno114 3.5 MW turbine. Simulating the NREL 5 MW turbine allows for a first evaluation of our PALM–FAST coupling approach based on characteristics of the NREL turbine reported in the literature. The basic test of the coupling with the NREL 5 MW turbine shows that the power curve obtained is very close to the one when using FAST alone. Furthermore, a validation with free-field measurement data for the eno114 3.5 MW turbine for a site in northern Germany is performed. The results show a good agreement with the free-field measurement data. Additionally, our coupling offers an enormous reduction of the computing time in comparison to an actuator line model, in one of our cases by 89 %, and at the same time an extensive output of turbine data.

Organic matter production by cyanobacteria blooms is a major environmental concern for the Baltic Sea, as it promotes the spread of anoxic zones. Partial pressure of carbon dioxide (pCO2) measurements carried out on Ships of Opportunity (SOOP) since 2003 have proven to be a powerful tool to resolve the carbon dynamics of the blooms in space and time. However, SOOP measurements lack the possibility to directly constrain depth-integrated net community production (NCP) in moles of carbon per surface area due to their restriction to the sea surface. This study tackles the knowledge gap through (1) providing an NCP best guess for an individual cyanobacteria bloom based on repeated profiling measurements of pCO2 and (2) establishing an algorithm to accurately reconstruct depth-integrated NCP from surface pCO2 observations in combination with modelled temperature profiles. Goal (1) was achieved by deploying state-of-the-art sensor technology from a small-scale sailing vessel. The low-cost and flexible platform enabled observations covering an entire bloom event that occurred in July–August 2018 in the Eastern Gotland Sea. For the biogeochemical interpretation, recorded pCO2 profiles were converted to CT*, which is the dissolved inorganic carbon concentration normalised to alkalinity. We found that the investigated bloom event was dominated by Nodularia and had many biogeochemical characteristics in common with blooms in previous years. In particular, it lasted for about 3 weeks, caused a CT* drawdown of 90 µmol kg−1, and was accompanied by a sea surface temperature increase of 10 ∘C. The novel finding of this study is the vertical extension of the CT* drawdown up to the compensation depth located at around 12 m. Integration of the CT* drawdown across this depth and correction for vertical fluxes leads to an NCP best guess of ∼1.2 mol m−2 over the productive period. Addressing goal (2), we combined modelled hydrographical profiles with surface pCO2 observations recorded by SOOP Finnmaid within the study area. Introducing the temperature penetration depth (TPD) as a new parameter to integrate SOOP observations across depth, we achieve an NCP reconstruction that agrees to the best guess within 10 %, which is considerably better than the reconstruction based on a classical mixed-layer depth constraint. Applying the TPD approach to almost 2 decades of surface pCO2 observations available for the Baltic Sea bears the potential to provide new insights into the control and long-term trends of cyanobacteria NCP. This understanding is key for an effective design and monitoring of conservation measures aiming at a Good Environmental Status of the Baltic Sea.

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There is growing concern about the rising levels of dissolved organic matter (DOM) in surface waters across the Northern hemisphere. However, only limited research has been conducted to unveil its precise origin. Compositional changes along terrestrial-aquatic pathways can help determine the terrestrial sources of DOM in streams. Stream water, soil water and soil horizons were sampled at four sites representing typical settings within a forested catchment in the Ore Mountains (Erzgebirge, Germany) from winter 2020 to spring 2022. The samples were analyzed using pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS). The resulting data were successfully subjected to semi-automatic processing of the molecular composition of DOM, reaching a percentage of identified peaks up to 98 %. Principal component analysis (PCA) and cluster analyses were carried out to identify distinct differences between DOM from the potential sources and in the streams. According to the PCA, organic soil horizons, soil water, and stream water samples could be clearly distinguished. Cluster analysis revealed that soil water DOM at all depths of Peats and deeper horizons of the Peaty Gleysols contributed the most to DOM in the stream section dominated by organic soils. In areas dominated by mineral soils, stream DOM resembled the DOM from the deeper mineral horizons of Cambisols and Podzols. Overall, our results suggested that most of the DOM exported from the catchment was derived from deeper mineral soil horizons, with little contribution of DOM derived from organic soils. Therefore, DOM fingerprint analysis of in-situ soil water proved to be a promising approach for tracing back the main sources of stream water DOM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

In up to 18% of patients, recurrence is observed after curative radical cystectomy. Tumour recurrence occurs in most cases in the locoregional lymph node, as well as in the remaining urinary tract, but very rarely in the orthotopic neobladder. We report a case of multiple recurrence of urothelial carcinoma solely in the orthotopic neobladder of a male patient, 10 years after surgery, without involvement of the urethra or upper urinary tract. Therefore, the patient underwent resection of the neobladder with conversion to a sigmoid conduit. Nevertheless approximately 6 months later the patient developed widespread metastases and died a few months later. Currently, no guidelines are available for the treatment of these rare cases. We present our experience, together with revision of the current literature on this issue., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

We report on a 66-year-old neuro-urological female patient who, three years after implantation of a neurostimulator, experienced cecal necrosis due to strangulation caused by the cable of the device., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: The choice between immunotherapy with a checkpoint inhibitor (CPI) and chemo-/immunotherapy (CIT) in patients with NSCLC stage IV is often discussed. There is some data that the effect of chemotherapy is influenced by TTF-1 expression. Little is known about the influence of thyreoid transcription factor 1 (TTF-1) expression on CIT and CPI therapy. We aimed to investigate the relationship between tumor TTF-1 expression and efficacy of CIT and CPI therapy., Patients and Methods: We retrospectively analysed 130 patients (age 68 ± 7 y) with NSCLC stage IV. Only patients with lung adenocarcinoma were included. Patients with ALK, ROS1, RET, MET, NTRK, EGFR, BRAF mutation were excluded. Patients were treated according to the guidelines with either CPI alone (pembrolizumab, nivolumab, atezolizumab, cemiplimab) or CIT (Carboplatin/Pemetrexed/Pembrolizumab, Carboplatin/Paclitaxel/Atezolizumab). We registered patients' characteristics including TTF-1 expression. Group 1 consisted of 40 patients with CPI and TTF-1 expression, group 2 were 26 patients with CPI and with no TTF-1 expression. Group 3 consisted of 41 patients with CIT and TTF-1 expression, group 4 were 23 patients with CIT and with no TTF-1 expression., Results: Group 1-4 showed comparable patients characteristics. Using cox-regression analysis, we found that TTF-1 expression resulted in an improved progression free survival (PFS) compared to patients with CPI and no TTF-1 expression (18 ± 3,15 vs. 5 ± 0,85 months, p = 0.004, 95% CI: 0,23 - 0,984). In patients, who were treated with CIT, PFS was also increased in patients with TTF-1 expression (9 ± 3,17 vs. 3 ± 0,399 months, p = 0.001, 95% CI: 0,23 - 0,85)., Conclusions: In a real-life setting, we found that TTF-1 expression is associated with an increased PFS. Patients with chemo-/immunotherapy and immunotherapy seem to have a better therapy response in pulmonary adenocarcinoma with TTF-1 expression., (© 2024. The Author(s).)

Peptide fibrillization is crucial in biological processes such as amyloid-related diseases and hormone storage, involving complex transitions between folded, unfolded, and aggregated states. We here employ light to induce reversible transitions between aggregated and nonaggregated states of a peptide, linked to the parathyroid hormone (PTH). The artificial light-switch 3-{[(4-aminomethyl)phenyl]diazenyl}benzoic acid (AMPB) is embedded into a segment of PTH, the peptide PTH 25-37 , to control aggregation, revealing position-dependent effects. Through in silico design, synthesis, and experimental validation of 11 novel PTH 25-37 -derived peptides, we predict and confirm the amyloid-forming capabilities of the AMPB-containing peptides. Quantum-chemical studies shed light on the photoswitching mechanism. Solid-state NMR studies suggest that β-strands are aligned parallel in fibrils of PTH 25-37 , while in one of the AMPB-containing peptides, β-strands are antiparallel. Simulations further highlight the significance of π-π interactions in the latter. This multifaceted approach enabled the identification of a peptide that can undergo repeated phototriggered transitions between fibrillated and defibrillated states, as demonstrated by different spectroscopic techniques. With this strategy, we unlock the potential to manipulate PTH to reversibly switch between active and inactive aggregated states, representing the first observation of a photostimulus-responsive hormone.

Microbiomes have emerged as a key component essential for maintaining the health of an organism. Additionally, the roles of microbiomes are multifaceted, some unique to specific body areas and organs while others, particularly the gut microbiome, having broader effects on the entire organism. Comparative literature is emerging that compares microbiomes across mammals and birds. Domestic poultry have been the most extensively studied relative to their role in production agriculture. These data have provided a great deal of information about the effects of diet and nutritional requirements relative to the gut microbiome, productivity, and resilience to diseases. Conversely, limited such research has been conducted on wild birds, despite them inhabiting a broad array of ecological niches and environments, providing a rich diversity in their adaptations to different habitats. Migratory birds and raptors are of particular interest. Migratory birds encounter a range of ecosystems and provide a link between allopatric populations. Raptors occupy high positions in the food chain, with potential exposure to biomagnification of environmental contaminants and pathogens. This review overviews our current understanding of the structure and function of avian microbiomes as related to avian health and reproduction in domestic and wild birds, highlighting knowledge gaps in need of further investigation for more effective conservation of rapidly declining avian populations.

In this work, core and core-shell microparticles formed by Ni-Mn-Co oxides with controlled composition were fabricated by an oxalate-assisted co-precipitation route, and their properties were analysed by diverse microscopy and spectroscopy techniques. The microparticles exhibit dimensions within the 2-6 μm range and mainly consist of NiO and NiMn 2 O 4 , the latter being promoted as the temperature of the treatment increases, especially in the shell region of the microparticles. Aspects such as the shell dimensions, the vibrational modes of the spinel compounds primarily observed in the shell region, the oxidation states of the cations at the surface of the microparticles, and the achievement of a Ni-rich 811 core and a Mn-rich 631 shell were thoroughly evaluated and discussed in this work.

Introduction: Due to a change in diagnostic prerequisites and the inclusion of novel diagnostic entities, the implementation of the 11th revision of the International Classification of Diseases (ICD-11) will presumably change prevalence rates of specific mental, behavioural or neurodevelopmental disorders and result in an altered prevalence rate for this grouping overall. This scoping review aims to summarise the characteristics of primary studies examining the prevalence of mental, behavioural or neurodevelopmental disorders based on ICD-11 criteria. The knowledge attained through this review will primarily characterise the methodological approaches of this research field and additionally assist in deciding which psychiatric diagnoses are-given the current literature-most relevant for subsequent systematic reviews and meta-analyses intended to approximate the magnitude of prevalence rates while providing a first glimpse of the range of expected (differences in) prevalence rates in these conditions., Methods and Analysis: MEDLINE, Embase, Web of Science and PsycINFO will be searched from 2011 to present without any language filters. This scoping review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Review guidelines.We will consider (a) cross-sectional and longitudinal studies (b) focusing on the prevalence rates of mental, behavioural or neurodevelopmental disorders (c) using ICD-11 criteria for inclusion. The omission of (a) case numbers and sample size, (b) study period and period of data collection or (c) diagnostic procedures on full-text level is considered an exclusion criterion.This screening will be conducted by two reviewers independently from one another and a third reviewer will be consulted with disagreements. Data extraction and synthesis will focus on outlining methodological aspects., Ethics and Dissemination: We intend to publish our review in a scientific journal. As the primary data are publicly available, we do not require research ethics approval., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The metal-resistant bacterium Cupriavidus metallidurans occurs in metal-rich environments. In auriferous soils, the bacterium is challenged by a mixture of copper ions and gold complexes, which exert synergistic toxicity. The previously used, self-made Au(III) solution caused a synergistic toxicity of copper and gold that was based on the inhibition of the CupA-mediated efflux of cytoplasmic Cu(I) by Au(I) in this cellular compartment. In this publication, the response of the bacterium to gold and copper was investigated by using a commercially available Au(III) solution instead of the self-made solution. The new solution was five times more toxic than the previously used one. Increased toxicity was accompanied by greater accumulation of gold atoms by the cells. The contribution of copper resistance determinants to the commercially available Au(III) solution and synergistic gold-copper toxicity was studied using single- and multiple-deletion mutants. The commercially available Au(III) solution inhibited periplasmic Cu(I) homeostasis, which is required for the allocation of copper ions to copper-dependent proteins in this compartment. The presence of the gene for the periplasmic Cu(I) and Au(I) oxidase, CopA, decreased the cellular copper and gold content. Transcriptional reporter gene fusions showed that up-regulation of gig , encoding a minor contributor to copper resistance, was strictly glutathione dependent. Glutathione was also required to resist synergistic gold-copper toxicity. The new data indicated a second layer of synergistic copper-gold toxicity caused by the commercial Au(III) solution, inhibition of the periplasmic copper homeostasis in addition to the cytoplasmic one.IMPORTANCEWhen living in auriferous soils, Cupriavidus metallidurans is not only confronted with synergistic toxicity of copper ions and gold complexes but also by different gold species. A previously used gold solution made by using aqua regia resulted in the formation of periplasmic gold nanoparticles, and the cells were protected against gold toxicity by the periplasmic Cu(I) and Au(I) oxidase CopA. To understand the role of different gold species in the environment, another Au(III) solution was commercially acquired. This compound was more toxic due to a higher accumulation of gold atoms by the cells and inhibition of periplasmic Cu(I) homeostasis. Thus, the geo-biochemical conditions might influence Au(III) speciation. The resulting Au(III) species may subsequently interact in different ways with C. metallidurans and its copper homeostasis system in the cytoplasm and periplasm. This study reveals that the geochemical conditions may decide whether bacteria are able to form gold nanoparticles or not., Competing Interests: The authors declare no conflict of interest.

Purpose: Despite the need to generate valid and reliable estimates of protection levels against SARS-CoV-2 infection and severe course of COVID-19 for the German population in summer 2022, there was a lack of systematically collected population-based data allowing for the assessment of the protection level in real time., Methods: In the IMMUNEBRIDGE project, we harmonised data and biosamples for nine population-/hospital-based studies (total number of participants n = 33,637) to provide estimates for protection levels against SARS-CoV-2 infection and severe COVID-19 between June and November 2022. Based on evidence synthesis, we formed a combined endpoint of protection levels based on the number of self-reported infections/vaccinations in combination with nucleocapsid/spike antibody responses ("confirmed exposures"). Four confirmed exposures represented the highest protection level, and no exposure represented the lowest., Results: Most participants were seropositive against the spike antigen; 37% of the participants ≥ 79 years had less than four confirmed exposures (highest level of protection) and 5% less than three. In the subgroup of participants with comorbidities, 46-56% had less than four confirmed exposures. We found major heterogeneity across federal states, with 4-28% of participants having less than three confirmed exposures., Conclusion: Using serological analyses, literature synthesis and infection dynamics during the survey period, we observed moderate to high levels of protection against severe COVID-19, whereas the protection against SARS-CoV-2 infection was low across all age groups. We found relevant protection gaps in the oldest age group and amongst individuals with comorbidities, indicating a need for additional protective measures in these groups., (© 2023. The Author(s).)

Purpose: Real-life effectiveness data on once-daily single-inhaler triple therapy (odSITT) with the inhaled corticosteroid fluticasone furoate (FF), the long-acting muscarinic antagonist umeclidinium (UMEC), and the long-acting β 2 -agonist vilanterol (VI) in patients with chronic obstructive pulmonary disease (COPD) are important to complement evidence from well-controlled randomized clinical trials. Effectiveness of odSITT was quantified by assessing health status and symptoms in usual care., Patients and Methods: ELLITHE was a single-country (Germany), multicenter, open-label, non-interventional effectiveness study between 2020 and 2022, evaluating the effect of treatment initiation with FF/UMEC/VI 100/62.5/25 µg once-daily via the ELLIPTA inhaler on improvements in clinical outcomes versus baseline in COPD patients. The primary endpoint was the change in the total COPD Assessment Test (CAT) score between baseline and month 12. Key secondary endpoints included change in CAT score over time, occurrence of exacerbations until month 12, changes in forced expiratory volume in one second (FEV 1 ), inhaler adherence, and safety., Results: Nine hundred and six patients were included (age 66.6 years, 55.6% male, mean FEV 1 52.6% of predicted, mean CAT 21.5 units, 1.4 exacerbations/year pre-study). About 63.9% of patients were escalated from dual therapies, and 18% were switched from multiple-inhaler triple therapies. Reductions in CAT score at month 12 were statistically significant and above the threshold of clinical importance (-2.6 units; p < 0.0001). CAT score also improved at interim visits. CAT improvements were more pronounced in patients with high baseline scores and better inhaler adherence. Exacerbations during follow-up were rare (0.2 events/year) compared to pre-study (1.4 events/year). FEV 1 was improved by 93 mL (p < 0.0001). No new safety effects were observed., Conclusion: In usual care, treatment with odSITT resulted in significant and clinically relevant improvements of CAT score and FEV 1 in COPD patients, regardless of the occurrence of exacerbations. These findings challenge the current guideline recommendations for SITT only in patients experiencing exacerbations., Competing Interests: Kai-Michael Beeh has received personal and/or institutional compensation for clinical research, consulting, lecturing fees from AstraZeneca, Boehringer Ingelheim, Bosch AG, GSK, Novartis, Menarini/Berlin Chemie and Chiesi; consulting and lecturing fees from Sanofi and Elpen; and consulting fees from Sterna. The authors report no other conflicts of interest in this work., (© 2024 Beeh et al.)

Early identification and intervention of individuals with an increased risk for bipolar disorder (BD) may improve the course of illness and prevent long‑term consequences. Early-BipoLife, a multicenter, prospective, naturalistic study, examined risk factors of BD beyond family history in participants aged 15-35 years. At baseline, positively screened help-seeking participants (screenBD at-risk) were recruited at Early Detection Centers and in- and outpatient depression and attention-deficit/hyperactivity disorder (ADHD) settings, references (Ref) drawn from a representative cohort. Participants reported sociodemographics and medical history and were repeatedly examined regarding psychopathology and the course of risk factors. N = 1,083 screenBD at-risk and n = 172 Ref were eligible for baseline assessment. Within the first two years, n = 31 screenBD at-risk (2.9 %) and none of Ref developed a manifest BD. The cumulative transition risk was 0.0028 at the end of multistep assessment, 0.0169 at 12 and 0.0317 at 24 months (p = 0.021). The transition rate with a BD family history was 6.0 %, 4.7 % in the Early Phase Inventory for bipolar disorders (EPIbipolar), 6.6 % in the Bipolar Prodrome Interview and Symptom Scale-Prospective (BPSS-FP) and 3.2 % with extended Bipolar At-Risk - BARS criteria). In comparison to help-seeking young patients from psychosis detection services, transition rates in screenBD at-risk participants were lower. The findings of Early-BipoLife underscore the importance of considering risk factors beyond family history in order to improved early detection and interventions to prevent/ameliorate related impairment in the course of BD. Large long-term cohort studies are crucial to understand the developmental pathways and long-term course of BD, especially in people at- risk., Competing Interests: Declaration of Competing Interest JM, KLB, CB, KL, CS, JM, GJ, AJF, ML, AB, AR, SM, TS, TK, IF, AJ, UD, SKÖ, PFP, LMH, PR, SB, PM, BM and AP state to have no conflict of interest. SKS has received author's and advisory honoraria from Takeda/Shire and Medice Arzneimittel Pütter GmbH in the last 3 years. AR serves on advisory boards and receives speaker's honoraria from Medice, Shire/Takeda, Janssen, neuraxpharm, Servier and SAGE. MB has received grant support from the Deutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung, and the European Commission. He served as a consultant to GH Research, Janssen-Cilag, neuraxpharm, Novartis, Shire International, Sunovion, and Takeda, and received fees from Aristo, Hexal, Janssen-Cilag, and Sunovion. CU Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: A recent multiregional whole-exome sequencing of 48 tumour samples from 9 gastric adenocarcinomas discovered PCLO mutations in 23 (47.9%) tumour samples. Based on that unexpected high prevalence of PCLO mutations, we hypothesized a tumour biological significance of PCLO in gastric cancer (GC)., Methods: Tumour samples (whole tissue sections) obtained from 466 patients resected for therapy-naive GC were stained with an anti-PCLO antibody. The histoscore for tumour cells and the presence of immunostaining of stromal cells and tumour vessels was documented for each case. An algorithm for PCLO immunopositivity was formed and correlated with clinicopathological patient characteristics., Results: 175 GCs were classified as PCLO positive within tumour cells, and 291 as negative. Stromal cells were positive for PCLO in 106 cases and tumour vessels in 84. PCLO-positive GCs more often showed an intestinal phenotype, a lower T category and were more commonly associated with Helicobacter pylori infection. A separate analysis of PCLO expression in intestinal and diffuse type GCs, respectively, showed no significant correlations. Patients with PCLO negative/low tumour cells showed a shortened overall (14.0 ± 1.4 vs. 16.0 ± 1.8 months) and tumour-specific survival (15.0 ± 1.6 months vs. 17.9 ± 3.6). Comparison of PCLOs genotype with its phenotype in 48 tumour samples obtained from nine cases showed no direct correlations with missense mutations., Conclusion: Our data provide evidence that PCLO is differentially expressed in GC and might delay tumour progression., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The etiology of chylous ascites is multifactorial. Malignant diseases, cirrhosis, trauma, lymphomatic abnormalities and mycobacteriosis are the most common causes. In NSCLC, chylous ascites is observed with peritoneal metastasis or abdominal lymph node metastases.RET alterations occur in 1-2% of NSCLC patients and since recently they can be treated in a targeted fashion.Our case report shows that new targeted therapies revolutionize prognosis, but confront us with the challenge of new and partly unknown side effects., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

The MDM2 proto-oncogene (MDM2) is a primary negative regulator of p53. The latter is frequently mutated in gastric cancer (GC). In the present study, we aimed to validate gene amplification, protein expression, and the putative tumor biological function of MDM2 in a well-characterized Western GC cohort. MDM2 amplification and protein expression were studied in a cohort of 327 GCs by fluorescence in situ hybridization (FISH) and immunohistochemistry. Gene amplification and protein expression were correlated with diverse clinicopathological patient characteristics including patient outcome. Immunohistochemically, 97 GCs (29.7%) were categorized as MDM2 positive and 230 GCs (70.3%) as negative. An amplification of MDM2 was found in 11 (3.4%) cases without evidence of intratumoral heterogeneity. Nine of these eleven (81.8%) cases showed MDM2 protein expression. MDM2 amplification correlated significantly with MDM2 protein expression (p < 0.001). On a case-by-case analysis, MDM2-amplified cases showed varied histological phenotypes and were most commonly microsatellite stable; EBV, HER2, and MET negative; and FGFR2 positive. A single case harbored both, MDM2 amplification and TP53 mutation. MDM2 amplification and MDM2 expression, respectively, did not correlate with overall or tumor-specific survival. Our targeted analysis of MDM2 in a well-characterized cohort of GC patients showed that MDM2 amplification is rare, of no specific histological phenotype, and may not be always mutually exclusive with TP53 mutations. Given the low number of cases, currently, no diagnostic or therapeutic recommendation related to MDM2 amplification can be given for GC of Western origin., (© 2023. The Author(s).)

Purpose: Lymphocyte activation gene 3 (LAG3) is thought to contribute to T cell exhaustion within the tumor microenvironment of solid tumors. This study aimed to analyze the spatial distribution of LAG3 + cells in relation to clinicopathological and survival data in a large set of 580 primary resected and neoadjuvantly treated gastric cancers (GC)., Methods: LAG3 expression was evaluated in tumor center and invasive margin using immunohistochemistry and whole-slide digital image analysis. Cases were divided into LAG3-low and LAG3-high expression groups based on (1) median LAG3 + cell density, (2) cut-off values adapted to cancer-specific survival using Cutoff Finder application., Results: Significant differences in spatial distribution of LAG3 + cells were observed in primarily resected GC, but not in neoadjuvantly treated GC. LAG3 + cell density showed evident prognostic value at following cut-offs: in primarily resected GC, 21.45 cells/mm 2 in tumor center (17.9 vs. 10.1 months, p = 0.008) and 208.50 cells/mm 2 in invasive margin (33.8 vs. 14.7 months, p = 0.006); and in neoadjuvantly treated GC, 12.62 cells/mm 2 (27.3 vs. 13.2 months, p = 0.003) and 123.00 cells/mm 2 (28.0 vs. 22.4 months, p = 0.136), respectively. Significant associations were found between LAG3 + cell distribution patterns and various clinicopathological factors in both cohorts. In neoadjuvantly treated GC, LAG3 + immune cell density was found to be an independent prognostic factor of survival (HR = 0.312, 95% CI 0.162-0.599, p < 0.001)., Conclusion: In this study, a higher density of LAG3 + cells was associated with favorable prognosis. Current results support the need for extended analysis of LAG3. Differences in the distribution of LAG3 + cells should be considered, as they could influence clinical outcomes and treatment responses., (© 2023. The Author(s).)

A 21-year-old athletic woman had been suffering from flank pain during fluid intake after sports for some time. Urological work-up revealed hydronephrosis with a "fishhook" shape and medial displacement of the ureter. This ureteral narrowing was studied ureterorenoscopically, bioptically and endoscopic-radiologically without the correct diagnosis of a retrocaval ureter being made. Therapeutically, a DJ stent was inserted several times, a balloon dilatation was performed under anaesthesia three times and finally a permanent DJ catheter was inserted. Due to the patient's dissatisfaction, an endoscopic endopyelotomy using Acucise was offered., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Delirium is one of the most common postoperative complications. Delayed initiation of treatment leads to an increased mortality rate within the first 90 days and to an increased need for post-hospital care. Similarly, neurocognitive disorders (NCDs) occur in a quarter of affected patients over the long-term. The use of evidence-based guideline recommendations can reduce incidence rates of delirium, shorten delirium duration, and prevent complications. Implementing delirium management according to evidence-based guideline recommendations requires a transformation process that integrates all stakeholders. In May 2017, the Federal Joint Committee (G-BA), the highest decision-making body in the German healthcare system, approved the quality contract (QC) as a new instrument for improving healthcare in Germany. With QC, hospitals have the opportunity to set up better conditions for the transformation process of delirium management, because with QC funding, initial hurdles can be more easily overcome, such as establishing and sustaining new structures or mobilizing resources. The cooperation of all stakeholders - but above all their shared understanding - of the need for transformation is crucial for the successful implementation of delirium management. The digitization of cross-departmental processes in particular is an elementary component in a modern transformation process. This creates new opportunities and processes that offer added value for patients and caregivers. Patients thus experience delirium management as a coherent interdisciplinary and multiprofessional concept that is implemented transparently, comprehensibly, and evidence-based., Competing Interests: Die Autoren nehmen Teil am Qualitätsvertrag zur Prävention des postoperativen Delirs bei der Versorgung älterer Patientinnen und Patienten (seit 01.04.2020) in Kooperation der Charité – Universitätsmedizin Berlin mit IQTIG und Barmer Ersatzkasse., (Thieme. All rights reserved.)

Background: The choice between immunotherapy with a checkpoint inhibitor (CPI) and chemo-/immunotherapy (CIT) in patients with NSCLC stage IV is often discussed. There are some data that the effect of CPI therapy is impaired by antimicrobial therapy (AMT). Little is known about the influence of AMT on CIT., Patients and Methods: We retrospectively analysed 114 patients (age 68 ± 8.5 years) with NSCLC stage IV. Patients were treated according to the guidelines with either CPI alone (pembrolizumab, nivolumab, atezolizumab, cemiplimab) or CIT (Carboplatin/Pemetrexed/Pembrolizumab, Carboplatin/Paclitaxel/Pembrolizumab). We registered patients' characteristics including presence and timing of AMT. Group 1 consisted of 42 patients with AMT in the month before CPI or CIT, group 2 were 49 patients with AMT during CPI or CIT, and group 3 were 64 patients without AMT and CPI or CIT., Results: Group 1-3 showed comparable patients characteristics. Using cox-regression analysis, we found that AMT in the month before CPI resulted in a decreased progression-free survival (PFS) compared to patients with CPI and no AMT (14 ± 1.02 vs. 4 ± 1.02 months, p = 0.002, 95% CI 1.88-9). In patients, who were treated with CIT, there was no difference in PFS in those with or without AMT in the month before therapy (10 ± 2.5 vs. 6 ± 1.2 months, p = 0.7). Interestingly, AMT during CIT or CPI therapy showed no effect on PFS., Conclusions: In a real-life setting, we found that AMT reduces PFS when given in the month before CIT therapy. AMT before or during CIT does not seem to influence PFS. As a consequence, AMT before start of therapy might be a factor that could lead to a preference of CIT instead of CPI in NSCLC stage IV patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: There is limited knowledge of whether cognitive-behavioral therapy (CBT) or second-generation antipsychotics (SGAs) should be recommended as the first-line treatment in individuals at clinical high risk for psychosis (CHRp)., Hypothesis: To examine whether individual treatment arms are superior to placebo and whether CBT is non-inferior to SGAs in preventing psychosis over 12 months of treatment., Study Design: PREVENT was a blinded, 3-armed, randomized controlled trial comparing CBT to clinical management plus aripiprazole (CM + ARI) or plus placebo (CM + PLC) at 11 CHRp services. The primary outcome was transition to psychosis at 12 months. Analyses were by intention-to-treat., Study Results: Two hundred eighty CHRp individuals were randomized: 129 in CBT, 96 in CM + ARI, and 55 in CM + PLC. In week 52, 21 patients in CBT, 19 in CM + ARI, and 7 in CM + PLC had transitioned to psychosis, with no significant differences between treatment arms (P = .342). Psychopathology and psychosocial functioning levels improved in all treatment arms, with no significant differences., Conclusions: The analysis of the primary outcome transition to psychosis at 12 months and secondary outcomes symptoms and functioning did not demonstrate significant advantages of the active treatments over placebo. The conclusion is that within this trial, neither low-dose aripiprazole nor CBT offered additional benefits over clinical management and placebo., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The gastric microbiome and inflammation play a key role in gastric cancer (GC) by regulating the immune response in a complex manner and by inflammatory events supporting carcinogenesis. Meprin β is a zinc endopeptidase and participates in tissue homeostasis, intestinal barrier function and immunological processes. It influences local inflammatory processes, dysbiosis and the microbiome. Here, we tested the hypothesis that meprin β is expressed in GC and of tumor biological significance., Patients and Methods: Four hundred forty whole mount tissue sections of patients with therapy-naive GC were stained with an anti-meprin β antibody. The histoscore and staining pattern were analyzed for each case. Following dichotomization at the median histoscore into a "low" and "high" group, the expression was correlated with numerous clinicopathological patient characteristics., Results: Meprin β was found intracellularly and at the cell membrane of GC. Cytoplasmic expression correlated with the phenotype according to Lauren, microsatellite instability and PD-L1 status. Membranous expression correlated with intestinal phenotype, mucin-1-, E-cadherin-, β-catenin status, mucin typus, microsatellite instability, KRAS mutation and PD-L1-positivity. Patients with cytoplasmic expression of meprin β showed a better overall and tumor-specific survival., Conclusions: Meprin β is differentially expressed in GC and has potential tumor biological relevance. It might function as a tumor suppressor or promotor depending on histoanatomical site and context., (© 2023. The Author(s).)

Introduction: Immune checkpoint inhibitors (ICI), e.g., targeting programmed cell death protein 1-ligand 1 (PD-L1) or its receptor PD-1, have markedly improved the therapy of many cancers but so far failed in pancreatic ductal adenocarcinoma (PDAC). Macrophages represent one of the most abundant immune cell populations within the tumor microenvironment (TME) of PDAC being able to either support or restrain tumor progression depending on their phenotype. To better understand treatment failure of PD-L1/PD-1 inhibitors in PDAC, this study examined PD-L1 expression in the context of a dynamic TME in PDAC with a particular focus on the impact of macrophages., Methods: Formalin-fixed and paraffin embedded tissue samples of primary PDAC tissues and corresponding liver metastases were used for immunohistochemical analyses. Serial sections were stained with antibodies detecting Pan-Cytokeratin, CD68, CD163, CD8, and PD-L1.To investigate whether the PD-1/PD-L1 axis and macrophages contribute to immune escape of PDAC cells, a stroma enriched 3D spheroid coculture model was established in vitro, using different PDAC cell lines and macrophages subtypes as well as CD8+ T cells. Functional and flow cytometry analyses were conducted to characterize cell populations., Results: Immunohistochemical analyses revealed that PD-L1 is mainly expressed by stroma cells, including macrophages and not PDAC cells in primary PDAC tissues and corresponding liver metastases. Notably, high local abundance of macrophages and strong PD-L1 staining were commonly found at invasion fronts of tumoral lesions between CD8+ T cells and tumor cells. In order to investigate whether PD-L1 expressing macrophages impact the response of PDAC cells to treatment with PD-L1/PD-1 inhibitors, we developed a spheroid model comprising two different PDAC cell lines and different ratios of in vitro differentiated primary M1- or M2-like polarized macrophages. In line with our in situ findings, high PD-L1 expression was observed in macrophages rather than PDAC cells, which was further increased by the presence of PDAC cells. The effector phenotype of co-cultured CD8+ T cells exemplified by expression of activation markers and release of effector molecules was rather enhanced by PDAC macrophage spheroids, particularly with M1-like macrophages compared to mono-culture spheroids. However, this was not associated with enhanced PDAC cell death. ICI treatment with either Durvalumab or Pembrolizumab alone or in combination with Gemcitabine hardly affected the effector phenotype of CD8+ T cells along with PDAC cell death. Thus, despite strong PD-L1 expression in macrophages, ICI treatment did not result in an enhanced activation and cytotoxic phenotype of CD8+ T cells., Conclusion: Overall, our study revealed novel insights into the interplay of PDAC cells and macrophages in the presence of ICI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Durvalumab was kindly provided by Astra Zeneca, which did play neither a role in the conceptualization and conduction of the study nor in the interpretation of the data., (Copyright © 2023 Daunke, Beckinger, Rahn, Krüger, Heckl, Schäfer, Wesch, Pilarsky, Eckstein, Hartmann, Röcken, Wandmacher and Sebens.)

Antibody-based blocking of vascular endothelial growth factor (VEGF) reduces choroidal neovascularization (CNV) and retinal edema, rescuing vision in patients with neovascular age-related macular degeneration (nAMD). However, poor response and resistance to anti-VEGF treatment occurs. We report that targeting the Notch ligand Jagged1 by a monoclonal antibody reduces neovascular lesion size, number of activated phagocytes and inflammatory markers and vascular leakage in an experimental CNV mouse model. Additionally, we demonstrate that Jagged1 is expressed in mouse and human eyes, and that Jagged1 expression is independent of VEGF signaling in human endothelial cells. When anti-Jagged1 was combined with anti-VEGF in mice, the decrease in lesion size exceeded that of either antibody alone. The therapeutic effect was solely dependent on blocking, as engineering antibodies to abolish effector functions did not impair the therapeutic effect. Targeting of Jagged1 alone or in combination with anti-VEGF may thus be an attractive strategy to attenuate CNV-bearing diseases., (© 2023. The Author(s).)

Background: Early during the SARS-CoV-2 pandemic, national population-based seroprevalence surveys were conducted in some countries; however, this was not done in Germany. In particular, no seroprevalence surveys were planned for the summer of 2022. In the context of the IMMUNEBRIDGE project, the GUIDE study was carried out to estimate seroprevalence on the national and regional levels., Methods: To obtain an overview of the population-wide immunity against SARS-CoV-2 among adults in Germany that would be as statistically robust as possible, serological tests were carried out using self-sampling dried blood spot cards in conjunction with surveys, one by telephone and one online. Blood samples were analyzed for the presence of antibodies to the S and N antigens of SARS-CoV-2., Results: Among the 15 932 participants, antibodies to the S antigen were detected in 95.7%, and to the N antigen in 44.4%. In the higher-risk age groups of persons aged 65 and above and persons aged 80 and above, anti-S antibodies were found in 97,4% and 98.8%, respectively. Distinct regional differences in the distribution of anti-S and anti-N antibodies emerged. Immunity gaps were found both regionally and in particular subgroups of the population. High anti-N antibody levels were especially common in eastern German states, and high anti-S antibody levels in western German states., Conclusion: These findings indicate that a large percentage of the adult German population has formed antibodies against the SARS-CoV-2 virus. This will markedly lower the probability of an overburdening of the health care system by hospitalization and high occupancy of intensive care units due to future SARS-CoV-2 waves, depending on the viral characteristics of then prevailing variants.

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Most cardiovascular deaths are caused by ischaemic heart diseases such as myocardial infarction (MI). Hereby atherosclerosis in the coronary arteries often precedes disease manifestation. Since tissue remodelling plays an important role in the development and progression of atherosclerosis as well as in outcome after MI, regulation of matrix metalloproteinases (MMPs) as the major ECM-degrading enzymes with diverse other functions is crucial. Here, we provide an overview of the expression profiles of MMPs in coronary artery and left ventricular tissue using publicly available data from whole tissue to single-cell resolution. To approach an association between MMP expression and the development and outcome of CVDs, we further review studies investigating polymorphisms in MMP genes since polymorphisms are known to have an impact on gene expression. This review therefore aims to shed light on the role of MMPs in atherosclerosis and MI by summarizing current knowledge from publically available datasets, human studies, and analyses of polymorphisms up to preclinical and clinical trials of pharmacological MMP inhibition., (© 2023. The Author(s).)

Introduction: Pancreatic ductal adenocarcinoma (PDAC) represents the 4 th most common cause of cancer-related deaths in Western countries. Most patients are diagnosed at advanced stages, often already with metastases. The main site of metastasis is the liver and hepatic myofibroblasts (HMF) play a pivotal role in metastatic outgrowth. Immune checkpoint inhibitors (ICI) targeting programmed death ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) improved treatment of several cancers but not of PDAC. Therefore, this study aimed to better understand the impact of HMF on PD-L1 expression and immune evasion of PDAC cells during liver metastasis., Methods: Formalin-fixed and paraffin embedded biopsy samples or diagnostic resection specimens from liver metastases of 15 PDAC patients were used for immunohistochemical analyses. Serial sections were stained with antibodies directed against Pan-Cytokeratin, αSMA, CD8, and PD-L1. To investigate whether the PD-1/PD-L1 axis and HMF contribute to immune escape of PDAC liver metastases, a stroma enriched 3D spheroid coculture model was established in vitro , using two different PDAC cell lines, HMF, and CD8 + T cells. Here, functional and flow cytometry analyses were conducted., Results: Immunohistochemical analysis of liver tissue sections of PDAC patients revealed that HMF represent an abundant stroma population in liver metastases, with clear differences in the spatial distribution in small (1500 µm) and large (> 1500 μm) metastases. In the latter, PD-L1 expression was mainly located at the invasion front or evenly distributed, while small metastases either lacked PD-L1 expression or showed mostly weak expression in the center. Double stainings revealed that PD-L1 is predominantly expressed by stromal cells, especially HMF. Small liver metastases with no or low PD-L1 expression comprised more CD8 + T cells in the tumor center, while large metastases exhibiting stronger PD-L1 expression comprised less CD8 + T cells being mostly located at the invasion front. HMF-enriched spheroid cocultures with different ratios of PDAC cells and HMF well mimicking conditions of hepatic metastases in situ . Here, HMF impaired the release of effector molecules by CD8 + T cells and the induction of PDAC cell death, an effect that was dependent on the amount of HMF but also of PDAC cells. ICI treatment led to elevated secretion of distinct CD8 + T cell effector molecules but did not increase PDAC cell death under either spheroid condition., Conclusion: Our findings indicate a spatial reorganization of HMF, CD8 + T cells, and PD-L1 expression during progression of PDAC liver metastases. Furthermore, HMF potently impair the effector phenotype of CD8 + T cells but the PD-L1/PD-1 axis apparently plays a minor role in this scenario suggesting that immune evasion of PDAC liver metastases relies on other immunosuppressive mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Durvalumab was kindly provided by AstraZeneca. AstraZeneca had no role in the design of the study, in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2023 Beckinger, Daunke, Aldag, Krüger, Heckl, Wesch, Schäfer, Röcken, Rahn and Sebens.)

Background: Recent studies have shown an association between certain subunits of the SWI/SNF complex with specific tumor characteristics in gastric cancer (GC). In an earlier study, we applied multiregional whole exome sequencing on multiple primary tumor samples and found alterations of the SWI/SNF complex in 78% of the cases. ERBB2, which encodes for Her2/neu, is a well-known predictive biomarker used to guide the treatment of GC in the palliative setting. SMARCE1, which encodes for a subunit of the SWI/SNF complex, is localized in close genetic proximity to ERBB2., Aim: As little is known about the significance of the SWI/SNF complex in GC biology and the potential relationship between ERBB2 and SMARCE1 upregulation, we examined the expression patterns of SMARCA4 and SMARCE1, two mutually exclusive catalytic ATPase subunits of the SWI/SNF complex, in a well characterized GC cohort., Materials and Methods: The expression of SMARCA4 and SMARCE1 was studied by immunohistochemistry in connection with clinicopathological patient characteristics in a cohort of 468 GCs. Digital droplet polymerase chain reaction was performed for amplification analysis on ERBB2 and SMARCE1., Results: Immunohistochemical staining of whole-mount tissue sections found a diffusely "gray scale" expression of SMARCA4 in 446 (95.2%) GCs and of SMARCE1 in 463 (98.8%) GCs. The expression of SMARCA4 and SMARCE1 correlated significantly with ARID1A, p53, and microsatellite status. No correlation was found with the patient prognosis. The amplification analysis of SMARCE1 showed amplification in 4 of 34 cases. In 3 of 34 cases, SMARCE1 was co-amplified with ERBB2. We also found a co-expression of SMARCE1 and Her2/neu in a subset of patients., Conclusion: While the effect of a co-amplification is currently unknown, synergistic effects of SMARCE1 and Her2/neu overexpression should be explored in future studies, holding potential for an improved treatment of GC., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The rapid development of wind energy in southern Africa represents an additional threat to the already fragile populations of African vultures. The distribution of the vulnerable Cape Vulture Gyps coprotheres overlaps considerably with wind energy development areas in South Africa, creating conflicts that can hinder both vulture conservation and sustainable energy development. To help address this conflict and aid in the safe placement of wind energy facilities, we map the utilization distribution (UD) of this species across its distributional range. Using tracking data from 68 Cape Vultures collected over the last 20 years, we develop a spatially explicit habitat use model to estimate the expected UDs around known colonies. Scaling the UDs by the number of vultures expected to use each of the colonies, we estimate the Cape Vulture population utilization distribution (PUD) and determine its exposure to wind farm impacts. To complement our results, we model the probability of a vulture flying within the rotor sweep area of a wind turbine throughout the species range and use this to identify areas that are particularly prone to collisions. Overall, our estimated PUD correlates well with reporting rates of the species from the Southern African Bird Atlas Project, currently used to assess potential overlap between Cape Vultures and wind energy developments, but it adds important benefits, such as providing a spatial gradient of activity estimates over the entire species range. We illustrate the application of our maps by analyzing the exposure of Cape Vultures in the Renewable Energy Development Zones (REDZs) in South Africa. This application is a scalable procedure that can be applied at different planning phases, from strategic, nationwide planning to project-level assessments., (© 2023 The Authors. Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Acute Dyspnea: The leading symptom "acute dyspnea" and the causal underlying diseases have a high risk potential for an unfavorable course of treatment with a high letality. This overview of possible causes, diagnostic procedures and guideline-based therapy is intended to help implement a targeted and structured emergency medical care in the emergency department. The leading symptom "acute dyspnea" is present in 10% of prehospital and 4-7% of patients in the emergency department. The most common conditions in the emergency department with the leading symptom "acute dyspnea" are heart failure in 25%, COPD in 15%, pneumonia in 13%, respiratory disorders in 8%, and pulmonary embolism in 4%. In 18% of cases, the leading symptom "acute dyspnea" is sepsis. The in-hospital letality is high and amounts to 9%. In critically ill patients in the non-traumatologic resuscitation room, respiratory disorders (B-problems) are present in 26-29%. In addition to cardiovascular disease, noncardiovascular disease may underlie "acute dyspnea" and requires differential diagnostic consideration. A structured approach can contribute to a high degree of certainty in the clarification of the leading symptom "acute dyspnea"., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Purpose: Various surface roughness parameters are utilized to describe the surface in the tooth to ceramics abrasion and to assess the resulting wear. The use of three-dimensional parameters may offer a better estimation for wear and an improved deduced clinical surface treatment. The aim of this study was to determine the influence of various surface roughness parameters of zirconia and lithium disilicate ceramics on the wear of steatite antagonists., Material and Methods: Forty zirconia specimens with a diameter of 7 mm and a thickness of 3 mm and 40 lithium disilicate specimens with the dimensions 10×10×4 mm were each divided into five subgroups. Two subgroups were treated with different clinically established diamond burs; a third subgroup was treated with a silicone polishing set. Two additional subgroups were produced by glazing the surfaces after treatment. Surface roughness parameters were determined by laser scanning microscopy. All specimens underwent 1.2 million loading cycles using steatite antagonists. After regular intervals of cycles, precision impressions were made to assess the wear. The correlation between wear and different roughness parameters was evaluated using the Spearman correlation test., Results: For the glazed zirconia, unglazed zirconia, and glazed lithium disilicate specimens no significant correlations (p > 0.05) between the investigated roughness parameters and antagonist wear could be found. In the unglazed lithium disilicate groups, significant (p ≤ 0.05) correlations with steatite substance loss could be found for several roughness parameters after 1.2 million cycles., Conclusions: For lithium disilicate, it seems not sufficient to use only one roughness parameter to indicate the wear behavior of the surface. There was no correlation between wear and the tested roughness parameters of zirconia surfaces., (© 2022 The Authors. Journal of Prosthodontics published by Wiley Periodicals LLC on behalf of American College of Prosthodontists.)

Gastric cancer (GC) is the fifth most common cancer in the world with a poor prognosis. Both RNF43 and LRP1B function as tumor suppressors in the Wnt signaling pathway and have been described to be frequently mutated in GC. In this study of a large and well characterized cohort of 446 GCs we explored the significance of expression of RNF43 and LRP1B and their correlations with clinicopathological patient characteristics. Immunostaining of whole mount tissue sections was documented with the histoscore. Dichotomized at the median, we separated the cohort into a low/negative and a high/positive group of RNF43 and LRP1B expression, respectively. Apart from the entire cohort, we also examined the intestinal and diffuse type GCs separately. Regarding the entire cohort, the expression of RNF43 and LRP1B correlated significantly with the Lauren phenotype and with each other. Interestingly, differences were noted regarding RNF43 between the intestinal and diffuse type GCs. Survival analysis of the intestinal type GCs showed that RNF43 low/negative GCs tended to have a better outcome compared with RNF43 high/positive GCs [24.5 months overall survival (OS) and 25.0 months tumor-specific survival (TSS) vs. 14.1 months OS and 17.9 months TSS, respectively]. To the contrary, diffuse type GCs with RNF43 low/negative had a worse outcome compared with RNF43 high/positive GCs (12.9 months OS and 18.2 months TSS vs. 17.1 months OS and 21.5 months TSS, respectively). On multivariate analysis, RNF43 low/negative versus high/positive was an independent prognosticator of survival in diffuse type GC (hazard ratio 2.393 for OS and 2.398 for TSS). These data support the contention that the expression and biological effect of RNF43 and LRP1B in GC is context-dependent., (© 2023. The Author(s).)

The desert locust Schistocerca gregaria detects odorants through olfactory sensory neurons (OSNs) that are surrounded by non-neuronal support cells (SCs). OSNs and SCs are housed in cuticle structures, named sensilla found abundantly on the antenna in all developmental stages of the hemimetabolic insect. In insects, multiple proteins expressed by OSNs and SCs are indicated to play a pivotal role in the detection of odorants. This includes insect-specific members of the CD36 family of lipid receptors and transporters called sensory neuron membrane proteins (SNMPs). While the distribution pattern of the SNMP1 and SNMP2 subtypes in OSNs and SCs across different sensilla types has been elucidated for the adult S. gregaria antenna, their localization in cells and sensilla of different developmental stages is unclear. Here, we determined the SNMP1 and SNMP2 expression topography on the antenna of the first, third and fifth instar nymphs. Through FIHC experiments we found that in all developmental stages SNMP1 is expressed in OSNs and SCs of the trichoid and basiconic sensilla while SNMP2 is restricted to the SCs of the basiconic and coeloconic sensilla thus resembling the adult arrangement. Our results demonstrate that both SNMP types have defined cell- and sensilla-specific distribution patterns established already in the first instar nymphs and retained into the adult stage. This conserved expression topography underlines the importance of SNMP1 and SNMP2 in olfactory processes throughout the development of the desert locust., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V.)

Although lung and heart diseases often occur together, the focus in acute medical emergency care frequently lies on the treatment of the cardiological symptoms only. This leads to a repeated patient visit and an impaired quality of life. How can this treatment gap be closed?, Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

With quantum chemical calculations at the density functional theory level, we examined the structure and the stability of diactinyl monohydroxo complexes [(AnO 2 ) 2 (OH)] 3+/+ in aqueous solution for An = U(VI), Np(VI), and Np(V). In particular, this study contributes to understanding the hydrolysis of Np(VI) and Np(V), which is less well characterized than for U(VI). [(UO 2 ) 2 (OH)] 3+ is a known hydrolysis complex of U(VI) at low pH. Although not yet found in experiments, [(NpO 2 ) 2 (OH)] 3+ is suggested to exist due to the similarity between Np(VI) and U(VI) complexes, while [(NpO 2 ) 2 (OH)] + is a hypothetical species thus far. Our calculations suggest that the An(VI) complexes favor the parallel orientation of actinyls, whereas for the Np(V) complex a perpendicular arrangement is stabilized by hydrogen bonds between aqua ligands and the actinyl oxygen atoms. The Np(VI) complex [(NpO 2 ) 2 (OH)] 3+ features a structure and stability similar to its U(VI) analogue. From calculated formation constants for An(VI) diactinyl monohydroxo complexes, we find qualitative agreement with the experiment for U(VI). Both An(VI) complexes are only slightly less stable than the separate mononuclear constituents, the actinyl aqua and the monohydroxo complex. For the Np(V) species [(NpO 2 ) 2 (OH)] + , we calculated a considerably lower complexation constant than for its An(VI) analogues, but it is more stable against decay into its constituents. Thus, this complex may exist at about the pH where Np(V) hydrolysis starts at not too low Np(V) concentrations.

Background: Intratumoral heterogeneity (ITH) is a major problem in gastric cancer (GC). We tested Ki67 and tumor regression for ITH after neoadjuvant/perioperative chemotherapy., Methods: 429 paraffin blocks were obtained from 106 neoadjuvantly/perioperatively treated GCs (one to five blocks per case). Serial sections were stained with Masson's trichrome, antibodies directed against cytokeratin and Ki67, and finally digitalized. Tumor regression and three different Ki67 proliferation indices (PI), i.e., maximum PI (KiH), minimum PI (KiL), and the difference between KiH/KiL (KiD) were obtained per block. Statistics were performed in a block-wise (all blocks irrespective of their case-origin) and case-wise manner., Results: Ki67 and tumor regression showed extensive ITH in our series (maximum ITH within a case: 31% to 85% for KiH; 4.5% to 95.6% for tumor regression). In addition, Ki67 was significantly associated with tumor regression (p < 0.001). Responders (<10% residual tumor, p = 0.016) exhibited prolonged survival. However, there was no significant survival benefit after cut-off values were increased ≥20% residual tumor mass. Ki67 remained without prognostic value., Conclusions: Digital image analysis in tumor regression evaluation might help overcome inter- and intraobserver variability and validate classification systems. Ki67 may serve as a sensitivity predictor for chemotherapy and an indicator of ITH., (© 2022. The Author(s).)

Introduction: Lung cancer is most common in older patients; despite this, older patients are historically under-represented in clinical studies. Here we present data from GIDEON, a study undertaken in Germany in patients with epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) receiving first-line afatinib. GIDEON enrolled a high proportion of patients aged ≥70 years, providing an opportunity to study afatinib use in older patients., Materials and Methods: In GIDEON (NCT02047903), a prospective non-interventional study, patients with EGFRm+ NSCLC received first-line afatinib in routine clinical practice until disease progression, death or intolerable adverse events. Key objectives were twelve-month progression-free survival (PFS) rate and objective response rate (ORR). Overall survival (OS) and safety were also assessed. This post hoc analysis explores outcomes of patients grouped by age (≥70 and <70 years)., Results: In the 152 patients enrolled in GIDEON (69.7% female, 64.5%/22.4%/13.2% with Del19/L858R/other exon 18-21 mutations, 33.6% with brain metastases), the median age was 67 years (range 38-89) and 43.4% were aged ≥70 years. In the ≥70 years age group and the <70 years age group, twelve-month PFS rate was 58.9% and 43.9%, median PFS was 17.2 months and 10.6 months, ORR was 72.0% and 76.5%, twelve-month OS rate was 79.1% and 79.2%, 24-month OS rate was 52.0% and 61.7%, and median OS was 30.4 months and 27.4 months, respectively. In the ≥70 years age group and the <70 years age group, grade ≥3 adverse drug reactions (ADRs) were observed in 34.8% and 40.7% of patients, respectively; the most common were diarrhea (13.6% and 14.0%), acneiform dermatitis (7.6% and 7.0%), stomatitis (1.5% and 4.7%) and maculopapular rash (1.5% and 4.7%)., Discussion: Patients with EGFRm+ NSCLC aged ≥70 years showed clinical benefit from first-line afatinib with no unexpected safety signals, supporting the use of afatinib in this setting., Competing Interests: Declaration of Competing Interest Wolfgang M. Brueckl reports receiving lecture and educational event (personal) fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Pfizer, Roche Pharmaceuticals, and Takeda; receiving congress (personal) fees from Boehringer Ingelheim, AstraZeneca, and Roche Pharmaceuticals; and receiving advisory board fees (personal) from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharp & Dohme, Lilly Pharma, Bristol Myers Squibb, and Roche. Martin Reck reports serving on advisory councils or committees and receiving consulting fees from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Sanofi; and receiving speaker honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. Kai Neben reports receiving honoraria (personal fees) from Roche, Takeda, Amgen, Janssen, Pfizer, Bayer, Merck Sharp & Dohme, Bristol Myers Squibb, and Chugai. Frank Griesinger reports receiving support for scientific research from ASTRA, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Siemens, Amgen, GlaxoSmithKline, and Janssen; receiving honoraria for presentations from ASTRA, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Siemens, Amgen, GlaxoSmithKline, Janssen, and Sanofi; and advisory board participation for ASTRA, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Siemens, GlaxoSmithKline, Janssen, and Sanofi. Justyna Rawluk reports serving on advisory councils or committees for AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, and Takeda; and receiving consulting fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, and Takeda. Stefan Krüger reports receiving honoraria and grants or funds from Boehringer Ingelheim. Joachim H. Ficker reports receiving speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi Aventis, and Bristol Myers Squibb. Miriam Möller reports receiving consulting fees (consulting or advisory role) from Boehringer Ingelheim and Roche; and receiving payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Boehringer Ingelheim, Roche, AstraZeneca, and Merck Sharp & Dohme. Andrea Schueler is an employee of Boehringer Ingelheim Pharma GmbH & Co KG. Eckart Laack, Konrad Kokowski and Harald Schäfer report no potential conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)