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Background: In 2012, the German Lipoprotein Apheresis Registry (GLAR) was launched. Real-world data on lipoprotein apheresis (LA) treatment are now available for a time period of 11 years. All patients received the maximally tolerated lipid-lowering therapy, which included statins, ezetimibe, bempedoic acid, and either proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies or antisense therapy., Methods and Results: During the time period from 2012 to 2022, 92 German apheresis centers collected retrospective and prospective observational data of a total of 2,301 patients undergoing regular lipoprotein apheresis (LA) treatment of hypercholesterolemia or/and Lp(a)-hyperlipoproteinemia suffering from progressive atherosclerotic cardiovascular disease (ASCVD), with complete data sets of 1.125 patients, who were the subject of this analysis. More than 61,500 LA sessions are documented in the database. In 2022, all patients treated with LA demonstrated a significant immediate median reduction rate of LDL-C (68.8 %) and Lp(a) (72.9 %). Patient data were analyzed for the incidence rate of major coronary events (MACE) 1 and 2 years before the beginning of LA treatment (y-2 and y-1) and prospectively up to eleven years on LA treatment (y+1 to y+11). During the first two years of LA treatment (y+1 and y+2), a MACE reduction of 73 % was observed and continued to be low during y+3 to y+11, when all LA patients were analyzed. LA patients with only increased Lp(a) levels (Lp(a) ≥ 60 mg/dl (≥120 nmol/l) and an LDL-C < 100 mg/dl (<2.6 mmol/l)) had a higher MACE reduction (85 %; n = 443) in the first two years of LA treatment compared to LA patients with only increased LDL-C-levels (LDL-C ≥ 100 mg/dl (≥2.6 mmol/l); Lp(a) < 60 mg/dl (<120 nmol/l)) (53 %; n = 171). Adverse events of LA remained low (about 5 %) over the eleven years and mainly represented puncture problems (1.0 %). No side effects resulted in termination of LA therapy., Conclusions: The current analysis of GLAR data indicates that regular LA leads to very low incidence rates of cardiovascular events in patients with high LDL-C and/or high Lp(a) levels, progressive ASCVD, and maximally tolerated lipid-lowering medication, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition. Additionally, LA was safe with a low rate of adverse effects over an 11-year period. The number of enrolled patients and the duration of observation establish GLAR as the largest LA registry worldwide., 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 Elsevier B.V. All rights reserved.)

Purpose: Transplant patients are increasingly of childbearing age. Organ-related health as well as pregnancy-related risks require a standardized approach to family planning counseling. The aim of this study was to explore sex- and organ-related counseling differences and expectations in family planning to improve counseling services and reduce risks after transplantation., Methods: The study was designed as a cross-sectional, multi-center cohort study. A total of 251 participants aged between 18 and 45 years with a visceral or thoracic transplant completed a questionnaire on their attitude toward family planning and experience with medical consultation., Results: More female than male participants had a desire to have children. Males believed their transplantation-related medication had an influence on their fertility, while women worried it could harm their child. Contraceptive counseling was negated by 43.6% of the women and 73.4% of the men. Medical advice regarding family planning was highly requested by both sexes. Women felt more influenced in their family planning than men. Female thoracic organ recipients worried about a pregnancy more than visceral organ recipients. Women showed great awareness for pregnancy-related risks with the majority wanting to plan a pregnancy beforehand., Conclusion: The findings revealed a lack of contraceptive counseling and a lack of family planning advice by physicians., (© 2024. The Author(s).)

Photodegradation of plastic consumer products is known to accelerate weathering and facilitate the release of chemicals and plastic particles into the aquatic environment. However, these processes are complex. In our presented pilot study, eight plastic consumer products were leached in distilled water under strong ultraviolet (UV) light simulating eight months of Central European climate and compared to their respective dark controls (DCs). The leachates and formed plastic particles were exploratorily characterized using a range of chemical analytical tools to describe degradation and leaching processes. These techniques covered (a) microplastic analysis, showing substantial liberation of plastic particles further increased under UV exposure, (b) non-targeted mass spectrometric characterization of the leachates, revealing several hundreds of chemical features with typically only minor agreement between the UV exposure and the corresponding DCs, (c) target analysis of 71 organic analytes, of which 15 could be detected in at least one sample, and (d) metal(loid) analysis, which revealed substantial release of toxic metal(loid)s further enhanced under UV exposure. A data comparison with the US-EPA's ToxVal and ToxCast databases showed that the detected metals and organic additives might pose substantial health and environmental concerns, requiring further study and comprehensive impact assessments., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Covalent inhibition with electrophiles of suitable reactivity allows for prolonged inactivation of a targeted enzyme, in comparison to noncovalent inhibitors. To fine-tune covalently reacting groups, various computational workflows have been developed for reactivity prediction. Their results are typically evaluated based on in vitro assays that use cysteine, glutathione, or other model nucleophiles, but the relevance of the predictions for the situation in a particular enzyme environment remains under-investigated. Herein, we utilized a DFT-based computational method to assess the transferability of predicted reactivities to enzyme inhibition. For this, we designed and synthesized a set of covalent inhibitors of ChlaDUB1, a potential target to fight the pathogen Chlamydia trachomatis . We show that in the context of enzyme inhibition, geometrical congruence between ligands has to be taken into account when evaluating the reactivity of covalently reacting groups in respective drug discovery projects., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Aims: We aimed to test the hypothesis if combining coronary artery calcium score (Ca-score) as a quantitative anatomical marker of coronary atherosclerosis with high-sensitivity cardiac troponin as a quantitative biochemical marker of myocardial injury provided incremental value in the detection of functionally relevant coronary artery disease (fCAD) and risk stratification., Methods and Results: Consecutive patients undergoing myocardial perfusion single-photon emission computed tomography (MPS) without prior CAD were enrolled. The diagnosis of fCAD was based on the presence of ischaemia on MPS and coronary angiography; fCAD was centrally adjudicated in the diagnostic and prognostic domain. Diagnostic accuracy was evaluated using the area under the receiver-operating characteristic curve (AUC). The composite of cardiovascular death and non-fatal acute myocardial infarction (AMI) within 730 days was the primary prognostic endpoint. Among 1715 patients eligible for the diagnostic analysis, 399 patients had fCAD. The combination of Ca-score and high-sensitivity cardiac troponin T (hs-cTnT) had good diagnostic accuracy for the diagnosis of fCAD (AUC 0.79, 95% confidence interval (CI) 0.77-0.81), but no incremental value compared with the Ca-score alone (AUC 0.79, 95% CI 0.77-0.81, P = 0.965). Similar results were observed using high-sensitivity cardiac troponin I (AUC 0.80, 95% CI 0.77-0.82) instead of hs-cTnT. Among 1709 patients (99.7%) with available follow-up, 59 patients (3.5%) suffered the composite primary prognostic endpoint (non-fatal AMI, n = 34; CV death, n = 28). Both Ca-score and hs-cTnT had independent prognostic value. Increased risk was restricted to patients with elevation in both markers., Conclusion: The combination of the Ca-score with hs-cTnT increases the prognostic accuracy for future events but does not provide incremental value vs. the Ca-score alone for the diagnosis of fCAD., Study Registration: Clinical trial registration: NCT00470587., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: The aim of this study was to collect and analyze information from pregnancies of organ transplanted women and partners of organ transplanted men. The goal was to enhance counseling regarding pregnancy planning and management and to enable more targeted monitoring to improve maternal and child health., Methods: In this retrospective, multicenter cohort study, women and men aged 18 to 45 who had undergone organ transplantation in Germany, Austria, and Switzerland were surveyed about their pregnancies before and after transplantation by using a self-developed questionnaire., Results: Even through transplanted women planned their pregnancies more carefully than before transplantation, they still experienced more pregnancy complications afterward. The live birth rate for pregnancies of partners of transplanted men, especially men who received a thoracic organ, was lower compared to before transplantation. Furthermore, this study showed that pregnancies of the partners of male transplant recipients occurred significantly less by spontaneous conception in comparison to pregnancies of transplanted women., Conclusion: Pregnancies after organ transplantation are possible but associated with an increased risk of pregnancy complications. Therefore, early counseling for transplanted women and men who wish to have children, along with extensive monitoring during pregnancy, is necessary., (© 2024. The Author(s).)

Single-molecule localization microscopy (SMLM) enables imaging scientists to visualize biological structures with unprecedented resolution. Particularly powerful implementations of SMLM are capable of three-dimensional, multicolor and high-throughput imaging and can yield key biological insights. However, widespread access to these technologies is limited, primarily by the cost of commercial options and complexity of de novo development of custom systems. Here we provide a comprehensive guide for interested researchers who wish to establish a high-end, custom-built SMLM setup in their laboratories. We detail the initial configuration and subsequent assembly of the SMLM, including the instructions for the alignment of all the optical pathways, the software and hardware integration, and the operation of the instrument. We describe the validation steps, including the preparation and imaging of test and biological samples with structures of well-defined geometries, and assist the user in troubleshooting and benchmarking the system's performance. Additionally, we provide a walkthrough of the reconstruction of a super-resolved dataset from acquired raw images using the Super-resolution Microscopy Analysis Platform. Depending on the instrument configuration, the cost of the components is in the range US$95,000-180,000, similar to other open-source advanced SMLMs, and substantially lower than the cost of a commercial instrument. A builder with some experience of optical systems is expected to require 4-8 months from the start of the system construction to attain high-quality three-dimensional and multicolor biological images., (© 2024. Springer Nature Limited.)

Background: The purpose of this study was to provide the 4-week prevalence estimates of mental disorders in newly diagnosed cancer patients in relation to socioeconomic status (SES)., Patients and Methods: We enrolled newly diagnosed patients with a confirmed solid tumor within 2 months of diagnosis. We calculated patients' SES on the basis of their educational level, professional qualification, income and occupational status. We used the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-Clinical Version (SCID-5-CV) to assess the 4-week prevalence of mental disorders in addition to a comorbidity questionnaire to assess the level of physical impairment., Results: We identified a total of 1702 patients with mixed cancers after reviewing their medical records and contacting them in person or by post due to coronavirus pandemic patient safety restrictions. 1030 patients (53.2% men, mean age 60.2 years) had completed SCID-5-CV. When weighted according to the SES distribution to account for over- and under-sampling of SES groups, 20.9% [95% confidence interval (CI) 18.1% to 23.6%] of patients were diagnosed with any mental disorder. The most prevalent were depressive disorders (9.9%, 95% CI 7.9% to 11.9%), trauma and stress-related disorders (6.3%, 95% CI 4.7% to 7.9%) and anxiety disorders (4.2%, 95% CI 2.9% to 5.6%). We found no difference in any mental disorder between patients with high, medium or low SES. Multivariate logistic regression analyses revealed higher proportion of patients with any mental disorder in patients younger than 60 years [odds ratio (OR) 0.42; P < 0.001], in patients without a partner (OR 1.84; P < 0.001), in women with tumor in female genital organs (OR 2.45; P < 0.002) and in those with a higher level of impairment (OR 1.05, 95% CI 1.03-1.07; P < 0.001)., Conclusions: SES had no significant influence on mental comorbidity in early cancer survivorship., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear., Methods: We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin., Results: The study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease-like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice., Conclusions: In this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance. (Funded by Deutsche Forschungsgemeinschaft and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Upon infection by an intracellular pathogen, host cells activate apoptotic pathways to limit pathogen replication. Consequently, efficient proliferation of the obligate intracellular pathogen Chlamydia trachomatis , a major cause of trachoma and sexually transmitted diseases, depends on the suppression of host cell apoptosis. C. trachomatis secretes deubiquitinase ChlaDUB1 into the host cell, leading among other interactions to the stabilization of antiapoptotic proteins and, thus, suppression of host cell apoptosis. Targeting the bacterial effector protein may, therefore, lead to new therapeutic possibilities. To explore the active site of ChlaDUB1, an iterative cycle of computational docking, synthesis, and enzymatic screening was applied with the aim of lead structure development. Hereby, covalent inhibitors were developed, which show enhanced inhibition with a 22-fold increase in IC 50 values compared to previous work. Comprehensive insights into the binding prerequisites to ChlaDUB1 are provided, establishing the foundation for an additional specific antichlamydial therapy by small molecules.

Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten., (© 2024. The Author(s).)

Background: The Sequential Organ Failure Assessment (SOFA) score is an important tool in diagnosing sepsis and quantifying organ dysfunction. However, despite emerging evidence of differences in sepsis pathophysiology between women and men, sex is currently not being considered in the SOFA score. We aimed to investigate potential sex-specific differences in organ dysfunction, as measured by the SOFA score, in patients with sepsis or septic shock and explore outcome associations., Methods: Retrospective analysis of sex-specific differences in the SOFA score of prospectively enrolled ICU patients with sepsis or septic shock admitted to one of 85 certified Swiss ICUs between 01/2021 and 12/2022., Results: Of 125,782 patients, 5947 (5%) were admitted with a clinical diagnosis of sepsis (2244, 38%) or septic shock (3703, 62%). Of these, 5078 (37% women) were eligible for analysis. A statistically significant difference of the total SOFA score on admission was found between women (mean 7.5 ± SD 3.6 points) and men (7.8 ± 3.6 points, Wilcoxon rank-sum p < 0.001). This was driven by differences in the coagulation (p = 0.008), liver (p < 0.001) and renal (p < 0.001) SOFA components. Differences between sexes were more prominent in younger patients < 52 years of age (women 7.1 ± 4.0 points vs men 8.1 ± 4.2 points, p = 0.004). No sex-specific differences were found in ICU length of stay (women median 2.6 days (IQR 1.3-5.3) vs men 2.7 days (IQR 1.2-6.0), p = 0.13) and ICU mortality (women 14% vs men 15%, p = 0.17)., Conclusion: Sex-specific differences exist in the SOFA score of patients admitted to a Swiss ICU with sepsis or septic shock, particularly in laboratory-based components. Although the clinical meaningfulness of these differences is unclear, a reevaluation of sex-specific thresholds for SOFA score components is warranted in an attempt to make more accurate and individualised classifications., (© 2024. The Author(s).)

Background: Older people receiving home-based care (HBC) often face barriers to access preventive oral health care (OHC) and dental treatments. Leading to deterioration of their oral healthcare. It is further deteriorated by factors such as increasing burden of systemic diseases, medicinal side effects, limited mobility, financial constraints and lack of professional OHC at home. Older people also struggle to maintain necessary daily oral hygiene, leading to malnutrition, weight loss, and a risk of a further health degradation. This cross-sectional survey aimed to investigate the oral health-related quality of life (OHRQoL) and their associated factors in HBC recipients., Methods: 5,280 older people (≥ 60 years) living in Hamburg, who were in need of care and insured with statutory health insurance DAK-Gesundheit received the questionnaire, which included the German version of the Oral Health Impact Profile (OHIP G-14) and, the EQ-5D health-related quality of life (HRQoL) measure as well as further questions regarding the extent of informal social support, subjective oral health status, oral health behaviour, subjective cognitive status, and socio-demographic variables., Results: The participants (n = 1,622) had a median age of 83.2 years, with 72.0% of the sample being female. Nearly two thirds of the sample reported that their independence or abilities were significantly impaired (care level 2). Regarding oral health impacts, 40.0% of the participants reported experiencing at least one of the fourteen possible prevalent impacts of the OHIP-G14 fairly often or very often. A multivariate regression model on the severity of oral health impacts revealed, that a better HRQoL, a positive perception of one's own dental status, fewer visits to dental practices, and no need for support in OHC were associated with better OHRQoL. Conversely, respondents with a negative perception of their oral health status, more frequent visits to a dental practice, a need for support in OHC, and subjective memory impairment showed poorer OHRQoL., Conclusions: The results highlight the risk for poor oral health among older people in HBC. We conclude that there is an urgent need to prioritise oral health, especially as poor oral health can further compromise the systemic wellbeing of these already care dependent population., (© 2024. The Author(s).)

The successful operation of a light microscopy core facility depends also on the initial setup of its infrastructure. This article covers the aspects of location selection and room planning and what environmental factors need to be considered. These include light, temperature, vibrations as well as the basic installations needed for microscope operation., (© 2024 The Authors. Journal of Microscopy published by John Wiley & Sons Ltd on behalf of Royal Microscopical Society.)

Background: There are no data on pharmacokinetics, pharmacodynamics, and immunogenicity of intravitreal aflibercept in preterm infants with retinopathy of prematurity (ROP). FIREFLEYE compared aflibercept 0.4 mg/eye and laser photocoagulation in infants with acute-phase ROP requiring treatment., Methods: Infants (gestational age ≤32 weeks or birthweight ≤1500 g) with treatment-requiring ROP in ≥1 eye were randomized 2:1 to receive aflibercept 0.4 mg or laser photocoagulation at baseline in this 24-week, randomized, open-label, noninferiority, phase 3 study. Endpoints include concentrations of free and adjusted bound aflibercept in plasma, pharmacokinetic/pharmacodynamic exploration of systemic anti-vascular endothelial growth factor effects, and immunogenicity., Results: Of 113 treated infants, 75 received aflibercept 0.4 mg per eye at baseline (mean chronological age: 10.4 weeks), mostly bilaterally (71 infants), and with 1 injection/eye (120/146 eyes). Concentrations of free aflibercept were highly variable, with maximum concentration at day 1, declining thereafter. Plasma concentrations of adjusted bound (pharmacologically inactive) aflibercept increased from day 1 to week 4, decreasing up to week 24. Six infants experienced treatment-emergent serious adverse events within 30 days of treatment; aflibercept concentrations were within the range observed in other infants. There was no pattern between free and adjusted bound aflibercept concentrations and blood pressure changes up to week 4. A low-titer (1:30), non-neutralizing, treatment-emergent anti-drug antibody response was reported in 1 infant, though was not clinically relevant., Conclusions: 24-week data suggest intravitreal aflibercept for treatment of acute-phase ROP is not associated with clinically relevant effects on blood pressure, further systemic adverse events, or immunogenicity., Gov Identifier: NCT04004208., (© 2024. The Author(s).)

Potentially hazardous particles from paints and functional coatings are an overlooked fraction of microplastic (MP) pollution since their accurate identification and quantification in environmental samples remains difficult. We have applied the most relevant techniques from the field of microplastic analysis for their suitability to chemically characterize anti-corrosion coatings containing a variety of polymer binders (LDIR, Raman and FTIR spectroscopy, Py-GC/MS) and inorganic additives (ICP-MS/MS). We present the basis of a possible toolbox to study the release and fate of coating particles in the (marine) environment. Our results indicate that, due to material properties, spectroscopic methods alone appear to be unsuitable for quantification of coating/paint particles and underestimate their environmental abundance. ICP-MS/MS and an optimized Py-GC/MS approach in combination with multivariate statistics enables a straightforward comparison of the multi-elemental and organic additive fingerprints of paint particles. The approach can improve the identification of unknown particles in environmental samples by an assignment to different typically used coating types. In future, this approach may facilitate allocation of emission sources of different environmental paint/coating particles. Indeed, future work will be required to tackle various remaining analytical challenges, such as optimized particle extraction/separation of environmental coating particles., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Primary production is an important driver of marine carbon storage. Besides the major nutrient elements nitrogen, phosphorus, and silicon, primary production also depends on the availability of nutrient-type metals (e.g., Cu, Fe, Mo) and the absence of toxicologically relevant metals (e.g., Ni, Pb). Especially in coastal oceans, carbon storage and export to the open ocean is highly variable and influenced by anthropogenic eutrophication and pollution. To model future changes in coastal carbon storage processes, a solid baseline of nutrient and metal concentrations is crucial. The North Sea is an important shelf sea, influenced by riverine, atmospheric, Baltic Sea, and North Atlantic inputs. We measured the concentrations of dissolved nutrients (NH 4 + , NO 3 - , PO 4 3- , and SiO 4 4- ) and 26 metals in 337 water samples from various depths within the entire North Sea and Skagerrak. A principal component analysis enabled us to categorize the analytes into three groups according to their predominant behavior: tracers for seawater (e.g., Mo, U, V), recycling (e.g., NO 3 - , PO 4 3- , SiO 4 4- ), and riverine or anthropogenic input (e.g., Ni, Cu, Gd). The results further indicate an increasing P-limitation and increasing anthropogenic gadolinium input into the German Bight., (© 2024. The Author(s).)

The certified reference materials (CRMs) BCR-668 (mussel tissue), NCS ZC73034 (prawn), NIST SRM 1566a (oyster tissue) and NIST SRM 2976 (mussel tissue) were analyzed for their mass fractions of 23 elements using inductively coupled plasma tandem-mass spectrometry (ICP-MS/MS). This study focused on the quantification of selected technology-critical elements (TCEs), specifically rare earth elements (REE) and the less studied TCEs Ga, Ge, Nb, In and Ta. Microwave assisted closed vessel digestion using an acid mixture of HNO 3 , HCl and H 2 O 2 was applied to varying sample masses and two different microwave systems. Recoveries of 76% (Gd, NCS ZC73034) to 129% (Lu, BCR-668) were obtained for the REE and 83% (Ge, NCS ZC73034) to 127% (Nb, NCS ZC73034) for the less studied TCEs across all analyzed CRMs (compared to certified values) using the best-performing parameters. Mass fractions for all analyzed, non-certified elements are suggested and given with a combined uncertainty U (k = 2), including mass fractions for Ga (11 µg kg -1 ± 9 µg kg -1 to 67 µg kg -1 ± 8 µg kg -1 ) and In (0.4 µg kg -1 ± 0.3 µg kg -1 to 0.8 µg kg -1 ± 0.7 µg kg -1 ). This study provides mass fractions of possible new emerging contaminants and addresses the relevant challenges in quantification of less studied TCEs, thus allowing the application of existing CRMs for method validation in studies dealing with the determination of TCEs in seafood or other biota., (© 2023. The Author(s).)

Purpose: Cancer in children leads to changes in family life, which can also affect the stability and quality of the parents' relationships. Studies show that parents' educational level, duration of partnership until diagnosis, child's cancer, and grandparents' relationship stability may influence parental partnership. The aim of this study was to investigate the influence of childhood cancer on the stability and quality of parental relationships in Germany., Methods: N = 74 parents of children with cancer aged 28-65 years (M = 41.9, SD = 7.6) completed questions on the stability and quality of their partnership as well as parental distress, depression, and anxiety. Stability was compared with the separation rate in the general population, and quality was compared using norm data from the German version of the Quality of Marriage Index (QMI-D; Zimmermann et al., 2019). A regression model was developed to predict mothers' current partnership quality., Results: The proportion of separated and divorced people was 12.2 % compared to 14. % in the general population. Retrospectively assessed partnership quality at time of diagnosis was significantly lower than in the German general population (p < .05). Higher anxiety proved to be the most significant predictor of maternal lower partnership satisfaction assessed at the time of the survey., Discussion: Parents of children with cancer did not show an increased separation rate. The partnership quality at the time of diagnosis was significantly lower, but was still above the cut-off of 34, suggesting predominant resilience of parental partnerships. However, some of parents showed significantly lower satisfaction. Future studies should identify parents who are more likely to experience a deterioration in partnership satisfaction or separation so that partnership interventions can be offered where appropriate., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The structure and texture of supraparticles determine their properties and performance, thus playing a critical role in research studies as well as industrial applications. The addition of salts is a well-known strategy to manipulate the colloidal stability of nanoparticles. In this study, this approach is used to tune the structure of spray-dried supraparticles. Three different salts (NaCl, CaCl 2 , and AlCl 3 ) were added to binary silica (SiO 2 ) nanoparticle dispersions (of 40 and 400 nm in size) to change their colloidal stability by lowering the electrostatic repulsion or enhancing the cation bridging. Dependent on the cation valence of the added salt and the nanoparticle size, the critical salt concentration, which yields nanoparticle agglomeration, is reached at different salt amounts. This phenomenon is exploited to tune the final structure of supraparticles - obtained by spray-drying binary dispersions - from core-shell to Janus-like to well-mixed structures. This consequently also tunes textural properties, like surface roughness and the pore system of the obtained supraparticles. Our results provide insights for controlling the structure of spray-dried supraparticles by manipulating the stability of binary nanoparticle dispersions, and they establish a framework for composite particle design., 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 © 2023 Elsevier Inc. All rights reserved.)

Increased particulate matter (PM) concentrations in our ambient air are the cause of various life-threatening diseases and consequently need to be reduced to nonhazardous levels. The natural PM removal capabilities of leaves inspired the development of a low-cost coating technology that exploits natural weather phenomena for its PM catching and removal processes. The herein presented coating is based on microparticle-filled silicone with optimized chemical and physical surface properties. Its surface roughness was tuned using differently sized spray-dried particles, and its surface contact angle was adjusted through silicone tensides, polar ether groups incorporated in the silicon backbone, and the used amount of spray-dried particles. In such a way, optimized silicone coatings showed in laboratory experiments improved catching abilities (>300% relative to glass surfaces), a full retention of adsorbed PM during wind events, and the formation of large PM aggregates. Upon (simulated) rain events, these coatings were regenerated, and the content of harmful PM of various sizes dispersed in water was reduced between ∼73 and 100%. Furthermore, an outdoor test over 100 days showed the functioning of the coating under real-world conditions. These regenerative coatings are readily applicable on diverse surfaces and do not require any further technical infrastructure. Thus, they present an extension of the toolbox for PM reduction technologies.

Oncogene-induced senescence (OIS) is an important process that suppresses tumor development, but the molecular mechanisms of OIS are still under investigation. It is known that BRAF V600E -mutated melanocytes can overcome OIS and develop melanoma, but the underlying mechanism is largely unknown. Using an established OIS model of primary melanocytes transduced with BRAF V600E , YAP activity was shown to be induced in OIS as well as in melanoma cells compared to that in normal epidermal melanocytes. This led to the assumption that YAP activation itself is not a factor involved in the disruption of OIS. However, its role and interaction partners potentially change. As Wnt molecules are known to be important in melanoma progression, these molecules were the focus of subsequent studies. Interestingly, activation of Wnt signaling using AMBMP resulted in a disruption of OIS in BRAF V600E -transduced melanocytes. Furthermore, depletion of Wnt6, Wnt10b or β-catenin expression in melanoma cells resulted in the induction of senescence. Given that melanoma cells do not exhibit canonical Wnt/β-catenin activity, alternative β-catenin signaling pathways may disrupt OIS. Here, we discovered that β-catenin is an interaction partner of YAP on DNA in melanoma cells. Furthermore, the β-catenin-YAP interaction changed the gene expression pattern from senescence-stabilizing genes to tumor-supportive genes. This switch is caused by transcriptional coactivation via the LEF1/TEAD interaction. The target genes with binding sites for LEF1 and TEAD are involved in rRNA processing and are associated with poor prognosis in melanoma patients. This study revealed that an alternative YAP-Wnt signaling axis is an essential molecular mechanism leading to OIS disruption in melanocytes., (© 2024. The Author(s).)

In the context of the COVID-19 pandemic, there has been a scarcity of resources with various effects on the care of cancer patients. This paper provides an English summary of a German guideline on prioritization and resource allocation for colorectal and pancreatic cancer in the context of the pandemic. Based on a selective literature review as well as empirical and ethical analyses, the research team of the CancerCOVID Consortium drafted recommendations for prioritizing diagnostic and treatment measures for both entities. The final version of the guideline received consent from the executive boards of nine societies of the Association of Scientific Medical Societies in Germany (AWMF), 20 further professional organizations and 22 other experts from various disciplines as well as patient representatives. The guiding principle for the prioritization of decisions is the minimization of harm. Prioritization decisions to fulfill this overall goal should be guided by (1) the urgency relevant to avoid or reduce harm, (2) the likelihood of success of the diagnostic or therapeutic measure advised, and (3) the availability of alternative treatment options. In the event of a relevant risk of harm as a result of prioritization, these decisions should be made by means of a team approach. Gender, age, disability, ethnicity, origin, and other social characteristics, such as social or insurance status, as well as the vehemence of a patient's treatment request and SARS-CoV-2 vaccination status should not be used as prioritization criteria. The guideline provides concrete recommendations for (1) diagnostic procedures, (2) surgical procedures for cancer, and (3) systemic treatment and radiotherapy in patients with colorectal or pancreatic cancer within the context of the German healthcare system., (© 2024 S. Karger AG, Basel.)

Diatoms have long been used as living biological indicators for the assessment of water quality in lakes and rivers worldwide. While this approach benefits from the great diversity of these unicellular algae, established protocols are time-consuming and require specialized equipment. Here, this work 3D prints diatom-laden hydrogels that can be used as a simple multiplex bio-indicator for water assessment. The hydrogel-based living materials are created with the help of a desktop extrusion-based printer using a suspension of diatoms, cellulose nanocrystals (CNC) and alginate as bio-ink constituents. Rheology and mechanical tests are employed to establish optimum bio-ink formulations, whereas cell culture experiments are utilized to evaluate the proliferation of the entrapped diatoms in the presence of selected water contaminants. Bioprinting of diatom-laden hydrogels is shown to be an enticing approach to generate living materials that can serve as low-cost bio-indicators for water quality assessment., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

A novel GaPt-based supported catalytically active liquid metal solution (SCALMS) material is developed by exploiting the suprabead concept: Supraparticles, i.e. micrometer-sized particles composed of nanoparticles assembled by spray-drying, are bonded to millimeter-sized beads. The suprabeads combine macroscale size with catalytic properties of nanoscale GaPt particles entrapped in their silica framework.

Purpose: Psycho-oncological screening is required to identify distressed patients and direct them to psycho-oncological care. In practice, screening procedure and related communication are still insufficient due to various barriers on the side of the medical team. The aim of this study is to evaluate the specifically developed training (OptiScreen training) on screening from nurses' perspective., Methods: N = 72 nurses from visceral-oncological care at Hanover Medical School received the 6-h training, which consisted of three modules and targeted topics around screening, psycho-oncology and communication. The training was evaluated using a pre- and post-questionnaire assessing screening knowledge, uncertainties and further satisfaction outcomes., Results: Personal uncertainties were significantly reduced by the training (t(63) = - 13.32, p < .001, d = 1.67). General satisfaction with the training was achieved (62.0-98.6% satisfied with the training elements). Feasibility (69%) and general acceptance (94.3%) for the training were rated positively., Conclusion: The nurses rated the training as useful to reduce personal uncertainties regarding the screening process. Acceptability, feasibility and satisfaction with the training from the nursing perspective were achieved. The training contributes to minimizing barriers to inform about psycho-oncology and to recommend appropriate support services to patients., (© 2023. The Author(s).)

To evaluate potential metal emissions from offshore wind farms (OWFs), 215 surface sediment samples from different German North Sea OWFs taken between 2016 and 2022 were analyzed for their mass fractions of metals and their isotopic composition of Sr. For the first time, this study provides large-scale elemental data from OWFs of the previously proposed galvanic anode tracers Cd, Pb, Zn, Ga and In. Results show that mass fractions of the legacy pollutants Cd, Pb and Zn were mostly within the known variability of North Sea sediments. At the current stage the analyzed Ga and In mass fractions as well as Ga/In ratios do not point towards an accumulation in sediments caused by galvanic anodes used in OWFs. However, further investigations are advisable to evaluate long-term effects over the expected lifetime of OWFs, especially with regard to the current intensification of offshore wind energy development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anna Ebeling reports financial support was provided by Federal Maritime and Hydrographic Agency. Dominik Wippermann reports financial support was provided by Federal Maritime and Hydrographic Agency. This work was supported by the BSH through the projects OffChEm I and II (BSH contract codes: 10036781 and 10052123, Hereon contract codes: 17/2017 and 169/2021) and by the German Federal Ministry for Digital and Transport (BMDV) in the context of the BMDV Network of Experts. Ole Klein was funded by the European Metrology Program for Innovation and Research (EMPIR) project MetroCycleEU (Funder ID: 10.13039/100014132, Grant number: 20IND01 MetroCycleEU)., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Trace elements play a major role in biogeochemical cycles and oceanographic processes. To determine trace element concentrations, the dissolved and particulate phase are usually separated by filtration. However, the frequently used membrane filtration as well as sample storage can bias the dissolved elemental concentrations by adsorption or desorption/contamination. We present a comparison of two filtration methods for coastal and estuarine water samples (pressure filtration with Nuclepore™ polycarbonate filters, vacuum filtration with DigiFILTER™s) applied to aliquots of a large-volume coastal water sample that were stored at -18°C or 4°C for up to nine weeks. The filtrates were analyzed by seaFAST-ICP-MS for dissolved Cd, Ce, Co, Cu, Dy, Er, Eu, Fe, Ho, La, Mn, Mo, Nd, Pb, Pr, Sm, Tb, U, V, W, Y, and Zn. The filtration blanks of DigiFILTER™s (0.0006 ± 0.0010 ng L -1 for Ho to 110 ± 180 ng L -1 for Zn) were sufficiently low for quantification of all analyzed elements with good repeatability, enabling a fast and reliable filtration of large sample sets of coastal water. However, the findings also highlight the need to measure procedural blanks including the filtration instead of only the instrument blanks to validate results. Measured concentrations of both filtration methods did not differ significantly for Cd, Cu, Mo, U, V, W, Zn but for other investigated elements, the ratio between both methods was up to 1.8 for Ce and 4.1 for Fe. Within nine weeks of storage, the elemental concentrations decreased significantly, resulting in losses of 20% Mn in frozen samples and 63% Pb, 64% Co and 93% Mn in cooled samples. PRACTITIONER POINTS: Two fast and cheap filtration methods for coastal water samples were compared. Dissolved concentrations of 22 elements were measured by seaFAST-ICP-MS. The filtration method is important in addition to filter pore size. Filtration blanks need to be reported to maintain comparability between methods. Cool and frozen storage of water samples biases the dissolved metal concentration., (© 2023 The Authors. Water Environment Research published by Wiley Periodicals LLC on behalf of Water Environment Federation.)

Purpose: Anxiety in the perioperative period is not only an unpleasant emotional state, but can also negatively affect the outcomes and quality of life of surgical patients. The present study investigated anxiety in patients with gastrointestinal cancer scheduled for primary surgery., Methods: A total of 101 patients in four non-university surgical departments were included. Anxiety (GAD-7), depression (PHQ-9), distress (Distress thermometer), and illness perception (Brief IPQ) were assessed at four time points: first outpatient contact before surgery (t1), preoperative inpatient contact (t2), postoperative inpatient contact before hospital discharge (t3), and postoperative outpatient follow-up contact after 30 days (t4)., Results: 56% of patients had an episode of mild or moderate anxiety and 5% had an episode of severe anxiety and/or depression. Subjectively perceived anxiety and depression were highest at t1, followed by t3. 30% of patients had elevated anxiety and depression scores at t1. Regression analyses showed that high subjectively perceived mental distress at t1 was associated with higher anxiety scores at t3 and t4. Women, and younger women in particular, were significantly more likely to experience stress than men. Higher levels of subjectively perceived stress at t1 were associated with higher levels of anxiety at t3 and t4. Sociodemographic factors were not relevant predictors of anxiety., Conclusion: Anxiety and depression appear to be a persistent problem during the perioperative course in patients with gastrointestinal tumors. Identifying patients at risk for clinically relevant anxiety and depression remains a particular challenge. The results confirm the relevance of repeated screening for mental distress., (© 2023. The Author(s).)

Study Objective: The diagnostic performance of T-wave amplitudes for the detection of myocardial infarction is largely unknown. We aimed to address this knowledge gap., Methods: T-wave amplitudes were automatically measured in 12-lead ECGs of patients presenting with acute chest discomfort to the emergency department within a prospective diagnostic multicenter study. The final diagnosis was centrally adjudicated by 2 independent cardiologists. Patients with left ventricular hypertrophy, complete left bundle branch block, or paced ventricular depolarization were excluded. The performance for lead-specific 95th-percentile thresholds were reported as likelihood ratios (lr), specificity, and sensitivity., Results: Myocardial infarction was the final diagnosis in 445 (18%) of 2457 patients. In most leads, T-wave amplitudes tended to be greater in patients without myocardial infarction than those with myocardial infarction, and T-wave amplitude exceeding the 95th percentile had positive and negative lr close to 1 or with confidence intervals (CIs) crossing 1. The exceptions were leads III, aVR, and V1, which had positive lrs of 3.8 (95% CI, 2.7 to 5.3), 4.3 (95% CI, 3.1 to 6.0) and 2.0 (95% CI, 1.4 to 2.9), respectively. These leads normally have inverted T waves, so T-wave amplitude exceeding the 95th percentile reflects upright rather than increased-amplitude hyperacute T waves., Conclusion: Hyperacute T waves, when defined as increased T-wave amplitude exceeding the 95th percentile, did not provide useful information in diagnosing myocardial infarction in this sample., (Copyright © 2022 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: Obesity is a major global health problem which can be targeted with new mechanistic diverse pharmacological interventions. Here we evaluate a new long-acting secretin receptor agonist as a potential treatment for obesity., Methods: BI-3434 was designed as a secretin analog with stabilized peptide backbone and attached fatty acid-based half-life extension group. The peptide was evaluated in vitro for its ability to stimulate cAMP accumulation in a cell line stably expressing recombinant secretin receptor. On the functional level, stimulation of lipolysis in primary adipocytes after treatment with BI-3434 was determined. The ability of BI-3434 to activate secretin receptor in vivo was assessed in a cAMP reporter CRE-Luc mouse model. Furthermore, a diet-induced obesity mouse model was used to test the effects of BI-3434 on body weight and food intake following repeated daily subcutaneous administration alone and in combination with a GLP-1R agonist., Results: BI-3434 potently activated human secretin receptor. However, lipolysis was only weakly induced in primary murine adipocytes. BI-3434 had an extended half-life compared to endogenous secretin and activated target tissues like pancreas, adipose tissue, and stomach in vivo. BI-3434 did not lower food intake in lean or diet-induced obese mice, but it increased energy expenditure after daily administration. This led to a loss of fat mass, which did not translate in a significant effect on body weight. However, treatment in combination with a GLP-1R agonist led to a synergistic effect on body weight loss., Conclusions: BI-3434 is a highly potent and selective agonist of secretin receptor with an extended pharmacokinetic (PK) profile. Increased energy expenditure after daily treatment with BI-3434 suggests that secretin receptor is involved in metabolic regulation and energy homeostasis. Targeting secretin receptor alone may not be an efficient anti-obesity treatment, but could be combined with anorectic principles like GLP-1R agonists., 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 © 2023 Boehringer Ingelheim Pharma GmbH&Co.KG. Published by Elsevier GmbH.. All rights reserved.)

Background: The utility of clinical risk scores regarding prediction of major adverse cardiac events (MACE) is uncertain. We aimed to directly compare the prognostic performance of five established clinical risk scores as well as an unstructured integrated clinical judgment (ICJ) of the treating emergency department (ED) physician., Methods: Thirty-day MACE including all-cause death, life-threatening arrhythmia, cardiogenic shock, acute myocardial infarction (including the index event), and unstable angina requiring urgent coronary revascularization were centrally adjudicated by two independent cardiologists in patients presenting to the ED with acute chest discomfort in an international multicenter study. We compared the prognostic performance of the HEART-score, GRACE-score, T-MACS, TIMI-score, and EDACS, as well as unstructured integrated clinical judgment (ICJ) of the treating ED physician (visual analogue scale to estimate the probability of an acute coronary syndrome (ACS), ranging from 0-100)., Results: Among 4551 eligible patients, 1110/4551 patients (24.4%) had at least one MACE within 30 days. Prognostic accuracy was high and comparable for the HEART-score, GRACE-score, T-MACS, and ICJ (area under the curve (AUC) 0.85-0.87), but significantly lower and only moderate for the TIMI-score (AUC 0.79, p<0.001) and EDACS (AUC 0.74, p<0.001), resulting in sensitivities for the rule-out of 30-day MACE of 93-96%, 87% (p<0.001), and 72% (p<0.001), respectively., Conclusion: The HEART-score, GRACE-score, T-MACS, and unstructured ICJ of the treating physician, but not the TIMI-score or EDACS, performed well for the prediction of 30-day MACE and may be considered for routine clinical use., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Cerebral DSA is a routine procedure with few complications. However, it is associated with presumably clinically inapparent lesions detectable on diffusion-weighted MRI imaging (DWI lesions). However, there are insufficient data regarding incidence, etiology, clinical relevance, and longitudinal development of these lesions. This study prospectively evaluated subjects undergoing elective diagnostic cerebral DSA for the occurrence of DWI lesions, potentially associated clinical symptoms and risk factors, and longitudinally monitored the lesions using state-of-the-art MRI., Materials and Methods: Eighty-two subjects were examined by high-resolution MRI within 24 h after elective diagnostic DSA and lesion occurrence was qualitatively and quantitatively evaluated. Subjects' neurological status was assessed before and after DSA by clinical neurological examination and a perceived deficit questionnaire. Patient-related risk factors and procedural DSA data were documented. Subjects with lesions received a follow-up MRI and were questioned for neurological deficits after a median of 5.1 months., Results: After DSA, 23(28%) subjects had a total of 54 DWI lesions. Significantly associated risk factors were number of vessels probed, intervention time, age, arterial hypertension, visible calcified plaques, and less examiner experience. Twenty percent of baseline lesions converted to persistent FLAIR lesions at follow-up. After DSA, none of the subjects had a clinically apparent neurological deficit. Self-perceived deficits were nonsignificantly higher at follow-up., Conclusion: Cerebral DSA is associated with a considerable number of postinterventional lesions, some persisting as scars in brain tissue. Presumably because of the small lesion size and inconsistent location, no clinically apparent neurological deficits have been observed. However, subtle self-perceived changes may occur. Therefore, special attention is needed to minimize avoidable risk factors., (© 2023. The Author(s).)

The enzyme transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis. Active TG2 is located mainly extracellularly in the lamina propria but also in the villous enterocytes of the duodenum. The TG2 inhibitor ZED1227 is a promising drug candidate for treating CeD and is designed to block the TG2-catalyzed deamidation and crosslinking of gliadin peptides. Our aim was to study the accumulation of ZED1227 after oral administration of the drug. We studied duodenal biopsies derived from a phase 2a clinical drug trial using an antibody that detects ZED1227 when bound to the catalytic center of TG2. Human epithelial organoids were studied in vitro for the effect of ZED1227 on the activity of TG2 using the 5-biotin-pentylamine assay. The ZED1227-TG2 complex was found mainly in the villous enterocytes in post-treatment biopsies. The signal of ZED1227-TG2 was strongest in the luminal epithelial brush border, while the intensity of the signal in the lamina propria was only ~20% of that in the villous enterocytes. No signal specific to ZED1227 could be detected in pretreatment biopsies or in biopsies from patients randomized to the placebo treatment arm. ZED1227-TG2 staining co-localized with total TG2 and native and deamidated gliadin peptides on the enterocyte luminal surface. Inhibition of TG2 activity by ZED1227 was demonstrated in epithelial organoids. Our findings suggest that active TG2 is present at the luminal side of the villous epithelium and that inhibition of TG2 activity by ZED1227 occurs already there before gliadin peptides enter the lamina propria.

This study examines laser microdissection pressure catapulting (LMPC) as an innovative method for microplastic research. Laser pressure catapulting as part of commercially available LMPC microscopes enables the precise handling of microplastic particles without any mechanical contact. In fact, individual particles with sizes between several micrometers and several hundred micrometers can be transported over centimeter-wide distances into a collection vial. Therefore, the technology enables the exact handling of defined numbers of small microplastics (or even individual ones) with the greatest precision. Herewith, it allows the production of particle number-based spike suspensions for method validation. Proof-of-principle LMPC experiments with polyethylene and polyethylene terephthalate model particles in the size range from 20 to 63 µm and polystyrene microspheres (10 µm diameter) demonstrated precise particle handling without fragmentation. Furthermore, the ablated particles showed no evidence of chemical alteration as seen in the particles' IR spectra acquired via laser direct infrared analysis. We propose LMPC as a promising new tool to produce future microplastic reference materials such as particle-number spiked suspensions, since LMPC circumvents the uncertainties resulting from the potentially heterogeneous behavior or inappropriate sampling from microplastic suspensions. Furthermore, LMPC could be advantageous for the generation of very accurate calibration series of spherical particles for microplastic analysis via pyrolysis-gas chromatography-mass spectrometry (down to 0.54 ng), as it omits the dissolution of bulk polymers., (© 2023. The Author(s).)

The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the Ω-loop pocket of TEAD has previously been communicated. This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and off-target profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time., (© 2023 Wiley-VCH GmbH.)

Background: Persons with hereditary cancer syndromes (carriers) have a higher risk of developing cancer early. They are confronted with decisions regarding prophylactic surgeries, communication within their families, and childbearing. The present study aims to assess distress, anxiety, and depression in adult carriers and identify risk groups and predictors; clinicians can use to screen for particularly distressed persons., Methods: N = 223 participants (n = 200 women, n = 23 men) with different hereditary cancer syndromes affected and unaffected by cancer answered questionnaires measuring their distress, anxiety, and depression levels. The sample was compared to the general population using one-sample t-tests. The n = 200 women with (n = 111) and without cancer (n = 89) were then compared and predictors for increased levels of anxiety and depression were identified using stepwise linear regression analyses., Results: 66% reported clinical relevant distress, 47% reported clinical relevant anxiety, and 37% reported clinical relevant depression. Compared to the general population, carriers experienced increased distress, anxiety, and depression. Additionally, women with cancer suffered from more depressive symptoms than those without cancer. Past psychotherapy for a mental disorder and high distress were identified as predictors for increased anxiety and depression in female carriers., Conclusions: The results suggest that the psychosocial consequences of hereditary cancer syndromes are serious. Clinicians could regularly screen carriers regarding anxiety and depression. The NCCN Distress Thermometer can be combined with questions about past psychotherapy to identify especially vulnerable persons. Further studies are needed to develop psychosocial interventions., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Self-reported exercise capacity is a well-established prognostic measure in stable ambulatory patients with cardiac and pulmonary disease., Objectives: The authors aimed to directly compare the prognostic accuracy of quantified self-reported exercise capacity using the Duke Activity Status Index (DASI) with the established objective disease-severity marker B-type natriuretic peptide (BNP) in patients presenting with acute dyspnea to the emergency department., Methods: The DASI was obtained in a prospective multicenter diagnostic study recruiting unselected patients presenting with acute dyspnea to the emergency department. The prognostic accuracy of DASI and BNP for 90-day and 720-day all-cause mortality was evaluated using C-index., Results: Among 1,019 patients eligible for this analysis, 75 (7%) and 297 (29%) patients died within 90 and 720 days after presentation, respectively. Unadjusted hazard ratios (HRs) and multivariable adjusted hazard ratios (aHRs) for 90- and 720-day mortality increased continuously from the fourth (best self-reported exercise capacity) to the first DASI quartile (worst self-reported exercise capacity). For 720-day mortality the HR of the first quartile vs the fourth was 9.1 (95% CI, 5.5-14.9) vs (aHR: 6.1, 95% CI: 3.7-10.1), of the second quartile 6.4 (95% CI: 3.9-10.6) vs (aHR: 4.4, 95% CI: 2.6-7.3), while of the third quartile the HR was 3.2 (95% CI: 1.9-5.5) vs (aHR: 2.4, 95% CI: 1.4-4.0). The prognostic accuracy of the DASI score was high, and higher than that of BNP concentrations (720-day mortality C-index: 0.67 vs 0.62; P  = 0.024)., Conclusions: Quantification of self-reported subjective exercise capacity using the DASI provides high prognostic accuracy and may aid physicians in risk stratification. (Basics in Acute Shortness of Breath EvaLuation [BASEL V] Study [BASEL V]; NCT01831115)., Competing Interests: This study was supported by research grants from the 10.13039/501100001711Swiss National Science Foundation, the 10.13039/501100004362Swiss Heart Foundation, the 10.13039/100008375University of Basel, the 10.13039/100016015University Hospital Basel, Critical Diagnostics, 10.13039/100000046Abbott, BRAHMS, 10.13039/100004337Roche and 10.13039/100016946Singulex. None of those supporters had any role in study design, the conduct of the study, the analysis of the data, or the decision to submit this manuscript for publication. Dr Breidthardt has received research grants from the Swiss National Science Foundation, the University Hospital Basel, the Department of Internal Medicine, University Hospital Basel, Abbott, and Roche. Dr Mueller has received research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the University Hospital Basel, the University of Basel, Abbott, Beckman Coulter, Biomerieux, BRAHMS, Ortho Clinical, Quidel, Novartis, Roche, Siemens, Singulex, and Sphingotec. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Functionally relevant coronary artery disease (fCAD), causing symptoms of myocardial ischemia, can currently only be reliably detected with advanced cardiac imaging. Serum neurofilament light chain (sNfL) is a biomarker for neuro-axonal injury known to be elevated by cardiovascular (CV) risk factors and cerebrovascular small-vessel diseases. Due to their pathophysiological similarities with fCAD and the link to CV risk factors, we hypothesised that sNfL may have diagnostic and prognostic value for fCAD and adverse cardiovascular outcomes. Methods: Of the large prospective Basel VIII study (NCT01838148), 4'016 consecutive patients undergoing cardiac work-up for suspected fCAD were included (median age 68 years, 32.5% women, 46.9% with history of CAD). The presence of fCAD was adjudicated using myocardial perfusion imaging single-photon emission tomography (MPI-SPECT) and coronary angiography. sNfL was measured using a high-sensitive single-molecule array assay. All-cause and cardiovascular death, myocardial infarction (MI), and stroke/transient ischaemic attack (TIA) during 5-year follow-up were the prognostic endpoints. Results: The diagnostic accuracy of sNfL for fCAD as quantified by the area under the curve (AUC) was low (0.58, 95%CI 0.56-0.60). sNfL was strongly associated with age, renal dysfunction, and body mass index and was a strong and independent predictor of all-cause death, cardiovascular death, and stroke/TIA but not MI. Time-dependent AUC for cardiovascular-death at 1-year was 0.85, 95%CI 0.80-0.89, and 0.81, 95%CI 0.77-0.86 at 2-years. Conclusion: While sNfL concentrations did not show a diagnostic role for fCAD, in contrast, sNfL was a strong and independent predictor of cardiovascular outcomes, including all-cause death, cardiovascular death and stroke/TIA.

15 filtration samples were collected at eight locations onboard the RV Sonne (cruise SO279 in 2020) from 6 m water depth using a fractionated stainless-steel filtration unit. The size fraction > 300 μm was visually examined and potential microplastic particles were analyzed by ATR-FTIR spectroscopy. The treatment of size class 20 μm < d < 300 μm was based on enzymatic-oxidative microwave-assisted "one-pot" matrix digestion in conjunction with analysis of the microplastics by time-efficient LDIR imaging. Total number concentrations ranged from 47 to 2154 microplastic particles per m 3 (average for all stations: 500 ± 700 microplastic particles m -3 (1 SD; n = 8)). In total, 20 polymer types were identified. The most common polymer types were polyethylene terephthalate (20 %) and acrylates/polyurethane/varnish (15 %). 93 % of the detected microplastics were smaller than 100 μm in length. Analysis of sample replicates indicates high spatio-temporal variations in microplastic pollution within the investigated region., 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 © 2023. Published by Elsevier Ltd.)

Background: Short-term forecasts of infectious disease burden can contribute to situational awareness and aid capacity planning. Based on best practice in other fields and recent insights in infectious disease epidemiology, one can maximise the predictive performance of such forecasts if multiple models are combined into an ensemble. Here, we report on the performance of ensembles in predicting COVID-19 cases and deaths across Europe between 08 March 2021 and 07 March 2022., Methods: We used open-source tools to develop a public European COVID-19 Forecast Hub. We invited groups globally to contribute weekly forecasts for COVID-19 cases and deaths reported by a standardised source for 32 countries over the next 1-4 weeks. Teams submitted forecasts from March 2021 using standardised quantiles of the predictive distribution. Each week we created an ensemble forecast, where each predictive quantile was calculated as the equally-weighted average (initially the mean and then from 26th July the median) of all individual models' predictive quantiles. We measured the performance of each model using the relative Weighted Interval Score (WIS), comparing models' forecast accuracy relative to all other models. We retrospectively explored alternative methods for ensemble forecasts, including weighted averages based on models' past predictive performance., Results: Over 52 weeks, we collected forecasts from 48 unique models. We evaluated 29 models' forecast scores in comparison to the ensemble model. We found a weekly ensemble had a consistently strong performance across countries over time. Across all horizons and locations, the ensemble performed better on relative WIS than 83% of participating models' forecasts of incident cases (with a total N=886 predictions from 23 unique models), and 91% of participating models' forecasts of deaths (N=763 predictions from 20 models). Across a 1-4 week time horizon, ensemble performance declined with longer forecast periods when forecasting cases, but remained stable over 4 weeks for incident death forecasts. In every forecast across 32 countries, the ensemble outperformed most contributing models when forecasting either cases or deaths, frequently outperforming all of its individual component models. Among several choices of ensemble methods we found that the most influential and best choice was to use a median average of models instead of using the mean, regardless of methods of weighting component forecast models., Conclusions: Our results support the use of combining forecasts from individual models into an ensemble in order to improve predictive performance across epidemiological targets and populations during infectious disease epidemics. Our findings further suggest that median ensemble methods yield better predictive performance more than ones based on means. Our findings also highlight that forecast consumers should place more weight on incident death forecasts than incident case forecasts at forecast horizons greater than 2 weeks., Funding: AA, BH, BL, LWa, MMa, PP, SV funded by National Institutes of Health (NIH) Grant 1R01GM109718, NSF BIG DATA Grant IIS-1633028, NSF Grant No.: OAC-1916805, NSF Expeditions in Computing Grant CCF-1918656, CCF-1917819, NSF RAPID CNS-2028004, NSF RAPID OAC-2027541, US Centers for Disease Control and Prevention 75D30119C05935, a grant from Google, University of Virginia Strategic Investment Fund award number SIF160, Defense Threat Reduction Agency (DTRA) under Contract No. HDTRA1-19-D-0007, and respectively Virginia Dept of Health Grant VDH-21-501-0141, VDH-21-501-0143, VDH-21-501-0147, VDH-21-501-0145, VDH-21-501-0146, VDH-21-501-0142, VDH-21-501-0148. AF, AMa, GL funded by SMIGE - Modelli statistici inferenziali per governare l'epidemia, FISR 2020-Covid-19 I Fase, FISR2020IP-00156, Codice Progetto: PRJ-0695. AM, BK, FD, FR, JK, JN, JZ, KN, MG, MR, MS, RB funded by Ministry of Science and Higher Education of Poland with grant 28/WFSN/2021 to the University of Warsaw. BRe, CPe, JLAz funded by Ministerio de Sanidad/ISCIII. BT, PG funded by PERISCOPE European H2020 project, contract number 101016233. CP, DL, EA, MC, SA funded by European Commission - Directorate-General for Communications Networks, Content and Technology through the contract LC-01485746, and Ministerio de Ciencia, Innovacion y Universidades and FEDER, with the project PGC2018-095456-B-I00. DE., MGu funded by Spanish Ministry of Health / REACT-UE (FEDER). DO, GF, IMi, LC funded by Laboratory Directed Research and Development program of Los Alamos National Laboratory (LANL) under project number 20200700ER. DS, ELR, GG, NGR, NW, YW funded by National Institutes of General Medical Sciences (R35GM119582; the content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS or the National Institutes of Health). FB, FP funded by InPresa, Lombardy Region, Italy. HG, KS funded by European Centre for Disease Prevention and Control. IV funded by Agencia de Qualitat i Avaluacio Sanitaries de Catalunya (AQuAS) through contract 2021-021OE. JDe, SMo, VP funded by Netzwerk Universitatsmedizin (NUM) project egePan (01KX2021). JPB, SH, TH funded by Federal Ministry of Education and Research (BMBF; grant 05M18SIA). KH, MSc, YKh funded by Project SaxoCOV, funded by the German Free State of Saxony. Presentation of data, model results and simulations also funded by the NFDI4Health Task Force COVID-19 (https://www.nfdi4health.de/task-force-covid-19-2) within the framework of a DFG-project (LO-342/17-1). LP, VE funded by Mathematical and Statistical modelling project (MUNI/A/1615/2020), Online platform for real-time monitoring, analysis and management of epidemic situations (MUNI/11/02202001/2020); VE also supported by RECETOX research infrastructure (Ministry of Education, Youth and Sports of the Czech Republic: LM2018121), the CETOCOEN EXCELLENCE (CZ.02.1.01/0.0/0.0/17-043/0009632), RECETOX RI project (CZ.02.1.01/0.0/0.0/16-013/0001761). NIB funded by Health Protection Research Unit (grant code NIHR200908). SAb, SF funded by Wellcome Trust (210758/Z/18/Z)., Competing Interests: KS, HG, RG, HJ, RN, BP, FS, JD, DW, SA, AU, GG, ER, NR, DS, YW, NW, LW, JT, GO, TS, DT, LP, EK, JM, MB, NL, JM, JS, JW, JF, BL, IR, JB, RW, IV, VT, MS, MZ, CP, BR, NB, SM, LC, GF, IM, DO, PA, AM, VE, AK, DK, LP, BD, ML, SS, JD, SM, VP, GR, BB, GA, NP, GZ, WB, SH, TH, DS, MG, JA, DM, SA, EA, DL, CP, JB, AR, TZ, AK, JZ, FP, FD, MC, GL, PG, BT, FB, GJ, MM, AF, AS, PM, AA, BH, BL, MM, PP, SV, RB, FD, AG, KG, MG, BK, AM, KN, JN, MR, FR, MS, ES, JZ, JK, BP, KH, YK, MS, BP, MB, MF, RI, TK, TO, JB, SF No competing interests declared, PB, HG, SS, BS Affiliated with IEM, Inc. The author has no financial interests to declare

Background: Despite remarkable progress, cancer remains a life-threatening disease for millions of people worldwide, also resulting in significant psychosocial limitations. High-quality, comprehensive cancer care requires patient and family involvement and the provision of needs-based, targeted psychosocial services. Although progress has been made in understanding the occurrence of mental comorbidity and psychosocial distress in cancer patients, comparatively little is known about the course of psychological comorbidity and psychosocial distress in early survivorship among patients and their families. We therefore aim to estimate the prevalence of mental disorders according to the DSM-5, psychosocial distress, perceived needs for psychosocial support and utilization of psychosocial support offers in newly diagnosed cancer patients and their relatives, taking into account potential contributing biopsychosocial factors for the occurrence of psychological comorbidity., Methods/design: This study follows a prospective multi-center observational cohort design across four measurement time points: within 2 months after cancer diagnosis (t1), and in the follow-up period at 6 months (t2), at 12 months (t3), and at 18 months (t4) after t1. Patients older than 18 years who have a confirmed initial diagnosis of a malignant solid tumor and are scheduled for cancer treatment at one of the participating cancer centers are eligible for study participation. Relatives of eligible patients are also eligible for study participation if they are older than 18 years. Patients are interviewed using the Structured Clinical Interview for DSM-5 Disorders (SCID-5-CV). In addition, patients and relatives receive a set of validated questionnaires at each measurement time point, covering comorbid conditions and functional performance, perceived psychological distress and quality of life, partnership aspects and social relationships, supportive care needs and use of psychosocial support services, health literacy, and health behavior and meaning in life., Discussion: This prospective multi-center observational cohort study has a major focus on increasing quality of care and quality of life in cancer survivors through providing rigorous longitudinal data for the development and implementation of target group-specific psychosocial support services., Trial Registration: NCT04620564, date of registration 9/11/2020; DKG OnkoZert: Registrier-No.: ST-U134, date of registration 5/11/2021., 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., (Copyright © 2023 Mehnert-Theuerkauf, Hufeld, Esser, Goerling, Hermann, Zimmermann, Reuter and Ernst.)