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The number of discovered exoplanets now exceeds 5500 allowing statistical analyses of planetary systems. Multi-planet systems are mini-laboratories of planet formation and evolution, and analysing their system architectures can help us to constrain the physics of these processes. Recent works have found evidence of significant intrasystem uniformity in planet properties such as radius, mass, and orbital spacing, collectively termed 'peas in a pod' trends. In particular, correlations in radius and mass have been interpreted as implying uniformity in planet bulk density and composition within a system. However, the samples used to assess trends in mass tend to be small and biased. In this paper, we re-evaluate correlations in planet properties in a large sample of systems with at least two planets for which mass and radius have been directly measured, and therefore bulk density can be calculated. Our sample was assembled using the most up-to-date exoplanet catalogue data, and we compute the relevant statistics while using a procedure to 'weight' the data points according to measurement precision. We find a moderate correlation in radius and a weak correlation in the densities of adjacent planets. However, masses of neighbouring planets show no overall correlation in our main sample and a weak correlation among pairs of planets similar in size or pairs restricted to Mp<100 M⊕, Rp<10 R⊕. Similarly, we show that the intrasystem dispersion in radius is typically less than that in mass and density. We identify ranges in stellar host properties that correlate with stronger uniformity in pairs of adjacent planets: low Teff for planet masses, and low metallicity and old age for planet densities. Furthermore, we explore whether peas in a pod trends extend into planet compositions or interior structures. For small neighbouring planets with similar radii, we show that their masses and interior structures are often disparate, indicating that even within the same system, similarity in radii is not necessarily a good proxy for similarity in composition or the physical nature of the planets. [ABSTRACT FROM AUTHOR]

Although several porous carbon/graphene nanoribbons (GNRs) have been prepared, a direct comparison of the electronic properties between a nonporous GNR and its periodically perforated counterpart is still missing. Here, we report the synthesis of porous 12-atom-wide armchair-edged GNRs from a bromoarene precursor on a Au(111) surface via hierarchical Ullmann and dehydrogenative coupling. The selective formation of porous 12-GNRs was achieved through thermodynamic and kinetic reaction control combined with tailored precursor design. The structure and electronic properties of the porous 12-GNR were elucidated by scanning tunneling microscopy/spectroscopy and density functional theory calculations, revealing that the pores induce a 2.17 eV band gap increase compared to the nonporous 12-AGNR on the same surface.

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with systemic inflammation, obesity, metabolic syndrome, and gut microbiome changes. Increased trimethylamine-N-oxide (TMAO) levels are predictive for mortality in HFpEF. The TMAO precursor trimethylamine (TMA) is synthesized by the intestinal microbiome, crosses the intestinal barrier and is metabolized to TMAO by hepatic flavin-containing monooxygenases (FMO). The intricate interactions of microbiome alterations and TMAO in relation to HFpEF manifestation and progression are analyzed here., Methods: Healthy lean (L-ZSF1, n = 12) and obese ZSF1 rats with HFpEF (O-ZSF1, n = 12) were studied. HFpEF was confirmed by transthoracic echocardiography, invasive hemodynamic measurements, and detection of N-terminal pro-brain natriuretic peptide (NT-proBNP). TMAO, carnitine, symmetric dimethylarginine (SDMA), and amino acids were measured using mass-spectrometry. The intestinal epithelial barrier was analyzed by immunohistochemistry, in-vitro impedance measurements and determination of plasma lipopolysaccharide via ELISA. Hepatic FMO3 quantity was determined by Western blot. The fecal microbiome at the age of 8, 13 and 20 weeks was assessed using 16s rRNA amplicon sequencing., Results: Increased levels of TMAO (+ 54%), carnitine (+ 46%) and the cardiac stress marker NT-proBNP (+ 25%) as well as a pronounced amino acid imbalance were observed in obese rats with HFpEF. SDMA levels in O-ZSF1 were comparable to L-ZSF1, indicating stable kidney function. Anatomy and zonula occludens protein density in the intestinal epithelium remained unchanged, but both impedance measurements and increased levels of LPS indicated an impaired epithelial barrier function. FMO3 was decreased (- 20%) in the enlarged, but histologically normal livers of O-ZSF1. Alpha diversity, as indicated by the Shannon diversity index, was comparable at 8 weeks of age, but decreased by 13 weeks of age, when HFpEF manifests in O-ZSF1. Bray-Curtis dissimilarity (Beta-Diversity) was shown to be effective in differentiating L-ZSF1 from O-ZSF1 at 20 weeks of age. Members of the microbial families Lactobacillaceae, Ruminococcaceae, Erysipelotrichaceae and Lachnospiraceae were significantly differentially abundant in O-ZSF1 and L-ZSF1 rats., Conclusions: In the ZSF1 HFpEF rat model, increased dietary intake is associated with alterations in gut microbiome composition and bacterial metabolites, an impaired intestinal barrier, and changes in pro-inflammatory and health-predictive metabolic profiles. HFpEF as well as its most common comorbidities obesity and metabolic syndrome and the alterations described here evolve in parallel and are likely to be interrelated and mutually reinforcing. Dietary adaption may have a positive impact on all entities., (© 2024. The Author(s).)

Endothelial cell physiology is governed by its unique microenvironment at the interface between blood and tissue. A major contributor to the endothelial biophysical environment is blood hydrostatic pressure, which in mechanical terms applies isotropic compressive stress on the cells. While other mechanical factors, such as shear stress and circumferential stretch, have been extensively studied, little is known about the role of hydrostatic pressure in the regulation of endothelial cell behavior. Here we show that hydrostatic pressure triggers partial and transient endothelial-to-mesenchymal transition in endothelial monolayers of different vascular beds. Values mimicking microvascular pressure environments promote proliferative and migratory behavior and impair barrier properties that are characteristic of a mesenchymal transition, resulting in increased sprouting angiogenesis in 3D organotypic model systems ex vivo and in vitro. Mechanistically, this response is linked to differential cadherin expression at the adherens junctions, and to an increased YAP expression, nuclear localization, and transcriptional activity. Inhibition of YAP transcriptional activity prevents pressure-induced sprouting angiogenesis. Together, this work establishes hydrostatic pressure as a key modulator of endothelial homeostasis and as a crucial component of the endothelial mechanical niche., (© 2024. The Author(s).)

The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Stereotactic radiosurgery/radiotherapy (SRS/SRT) and novel systemic treatments, such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), have demonstrated to be effective in managing brain metastases in non-small cell lung cancer (NSCLC). However, the optimal treatment sequence of SRS/SRT and TKI/ICI remains uncertain. This retrospective monocentric analysis addresses this question by comparing the outcomes of patients with NSCLC brain metastases who received upfront SRS/SRT versus those who were initially treated with TKI/ICI., Methods: All patients treated with SRS/SRT and TKI/ICI for NSCLC brain metastases were collected from a clinical database. The patients who received first-line TKI or ICI for the treatment of brain metastases were then selected for further analysis. Within this cohort, a comparative analysis between upfront SRS/SRT and patients initially treated with TKI/ICI was conducted, assessing key parameters such as overall survival (OS), intracranial progression-free survival (iPFS) and treatment-related toxicity. Both OS and iPFS were defined as the time from SRS/SRT to either death or disease progression, respectively., Results: The analysis encompassed 54 patients, of which 34 (63.0%) patients received SRS/SRT and TKI/ICI as their first-line therapy. Of the latter, 17 (50.0%) patients received upfront SRS/SRT and 17 (50.0%) were initially treated with TKI/ICI; 24 (70.6%) received SRS/SRT and ICI, and 10 (29.4%) received SRS/SRT and TKI. The cohorts did not significantly differ in the univariable analyses for the following parameters: sex, age, histology, molecular genetics, disease stage at study treatment, performance status, number of brain metastases, treatment technique, tumor volume, target volume, disease progression, radiation necrosis, dosimetry. While no significant differences were found in terms of iPFS and OS between patients treated with upfront SRS/SRT and patients initially treated with TKI, upfront SRS/SRT demonstrated significantly superior OS when compared to patients initially treated with ICI (median OS not reached vs. 17.5 months; mean 37.8 vs. 23.6 months; P=0.03) with no difference in iPFS. No significant differences in treatment-related toxicity were observed among the cohorts., Conclusions: In this retrospective, single-center cohort study, patients treated with upfront SRS/SRT demonstrated significantly longer OS compared to patients initially treated with ICI in the cohort receiving first-line therapy for brain metastases. However, given the retrospective design and the limited cohort size, definitive conclusions cannot be drawn from these findings. Nevertheless, the results suggest that the timing of SRS/SRT may play an important role in treatment outcomes. Further investigation, preferably through prospective randomized trials, is warranted to provide more conclusive answers to this important question., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-132/coif). R.B. received Open Access Fund from University of Tübingen, and received honoraria from NovoCure for participating in invited meetings of specialized centers. C.B. received grants or contracts not related to this manuscript from Viewray, Brainlab and Elekta, and received support for attending meetings and/or travel from BMS, Roche, Merck, AstraZeneca and Viewray. F.M. received an unrestricted Research Institutional Grant from AstraZeneca, received honoraria from AstraZeneca, Novartis, Roche, Lilly, Elekta and Brainlab, and serves in the advisory board of AstraZeneca and Novartis. M.N. received payments from Brainlab and AstraZeneca for speaking services. The other authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

This study explored the coping experiences of mothers of children with disabilities during the COVID-19 pandemic in Israel. Semi-structured in-depth interviews were conducted with 14 mothers. The data were thematically analyzed to gain in-depth understanding of their coping experiences. The findings indicated that COVID-related restrictions disrupted the family routine and added a significant burden for the mothers as primary caregivers, and for the family system as a whole. Three distinct types of coping experiences arose from the analysis: surviving the crisis, controlling the crisis, and growing out of the crisis. Three key elements differentiated these three types: the perceptions of the meaning of the pandemic for parental roles and of the response of the education and welfare systems to the children's needs - in routine and during COVID-19; coping with the different pandemic challenges; and the implications of both COVID-19 and the mothers' coping strategies for the functional and emotional status of their children, themselves, and family relations. The results are discussed in light of models of family stress and coping, focusing on the tension between the mothers' caregiving role and maternal roles as warranting particular attention by professionals and policymakers., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Deep learning (DL)-enabled magnetic resonance imaging (MRI) reconstructions can enable shortening of breath-hold examinations and improve image quality by reducing motion artifacts. Prospective studies with DL reconstructions of accelerated MRI of the upper abdomen in the context of pancreatic pathologies are lacking. In a clinical setting, the purpose of this study is to investigate the performance of a novel DL-based reconstruction algorithm in T1-weighted volumetric interpolated breath-hold examinations with partial Fourier sampling and Dixon fat suppression (hereafter, VIBE-DixonDL). The objective is to analyze its impact on acquisition time, image sharpness and quality, diagnostic confidence, pancreatic lesion conspicuity, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR)., Methods: This prospective single-center study included participants with various pancreatic pathologies who gave written consent from January 2023 to September 2023. During the same session, each participant underwent 2 MRI acquisitions using a 1.5 T scanner: conventional precontrast and postcontrast T1-weighted VIBE acquisitions with Dixon fat suppression (VIBE-Dixon, reference standard) using 4-fold parallel imaging acceleration and 6-fold accelerated VIBE-Dixon acquisitions with partial Fourier sampling utilizing a novel DL reconstruction tailored to the acquisition. A qualitative image analysis was performed by 4 readers. Acquisition time, image sharpness, overall image quality, image noise and artifacts, diagnostic confidence, as well as pancreatic lesion conspicuity and size were compared. Furthermore, a quantitative analysis of SNR and CNR was performed., Results: Thirty-two participants were evaluated (mean age ± SD, 62 ± 19 years; 20 men). The VIBE-DixonDL method enabled up to 52% reduction in average breath-hold time (7 seconds for VIBE-DixonDL vs 15 seconds for VIBE-Dixon, P < 0.001). A significant improvement of image sharpness, overall image quality, diagnostic confidence, and pancreatic lesion conspicuity was observed in the images recorded using VIBE-DixonDL (P < 0.001). Furthermore, a significant reduction of image noise and motion artifacts was noted in the images recorded using the VIBE-DixonDL technique (P < 0.001). In addition, for all readers, there was no evidence of a difference in lesion size measurement between VIBE-Dixon and VIBE-DixonDL. Interreader agreement between VIBE-Dixon and VIBE-DixonDL regarding lesion size was excellent (intraclass correlation coefficient, >90). Finally, a statistically significant increase of pancreatic SNR in VIBE-DIXONDL was observed in both the precontrast (P = 0.025) and postcontrast images (P < 0.001). Also, an increase of splenic SNR in VIBE-DIXONDL was observed in both the precontrast and postcontrast images, but only reaching statistical significance in the postcontrast images (P = 0.34 and P = 0.003, respectively). Similarly, an increase of pancreas CNR in VIBE-DIXONDL was observed in both the precontrast and postcontrast images, but only reaching statistical significance in the postcontrast images (P = 0.557 and P = 0.026, respectively)., Conclusions: The prospectively accelerated, DL-enhanced VIBE with Dixon fat suppression was clinically feasible. It enabled a 52% reduction in breath-hold time and provided superior image quality, diagnostic confidence, and pancreatic lesion conspicuity. This technique might be especially useful for patients with limited breath-hold capacity., Competing Interests: Conflicts of interest and sources of funding: The authors of this manuscript declare relationships with the MR Applications Predevelopment, Siemens Healthcare GmbH, Erlangen, Germany. The co-authors, employed by Siemens Healthineers and Siemens Healthcare, supported the other authors with the technical development of the DL MR reconstruction but had no influence on its evaluation or on any aspect of this study. Patient data remained at all times under the control of the authors, who were not affiliated to Siemens., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Oxford Nanopore Technologies sequencing, also referred to as Nanopore sequencing, stands at the forefront of a revolution in clinical genetics, offering the potential for rapid, long read, and real-time DNA and RNA sequencing. This technology is currently making sequencing more accessible and affordable. In this comprehensive review, we explore its potential regarding precision cancer diagnostics and treatment. We encompass a critical analysis of clinical cases where Nanopore sequencing was successfully applied to identify point mutations, splice variants, gene fusions, epigenetic modifications, non-coding RNAs, and other pivotal biomarkers that defined subsequent treatment strategies. Additionally, we address the challenges of clinical applications of Nanopore sequencing and discuss the current efforts to overcome them., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Aging leads to biochemical and biomechanical changes in skin, with biological and functional consequences. Despite extensive literature on skin aging, there is a lack of studies which investigate the maturation of the tissue and connect the microscopic changes in the skin to its macroscopic biomechanical behavior as it evolves over time. The present work addresses this knowledge gap using multiscale characterization of skin in a murine model considering newborn, adult and aged mice. Monotonic uniaxial loading, tension relaxation with change of bath, and loading to failure tests were performed on murine skin samples from different age groups, complemented by inflation experiments and atomic force microscopy indentation measurements. In parallel, skin samples were characterized using histological and biochemical techniques to assess tissue morphology, collagen organization, as well as collagen content and cross-linking. We show that 1-week-old skin differs across nearly all measured parameters from adult skin, showing reduced strain stiffening and tensile strength, a thinner dermis, lower collagen content and altered crosslinking patterns. Surprisingly, adult and aged skin were similar across most biomechanical parameters in the physiologic loading range, while aged skin had lower tensile strength and lower stiffening behavior at large force values. This correlates with altered collagen content and cross-links. Based on a computational model, differences in mechanocoupled stimuli in the skin of the different age groups were calculated, pointing to a potential biological significance of the age-induced biomechanical changes in regulating the local biophysical environment of dermal cells. STATEMENT OF SIGNIFICANCE: Skin microstructure and the emerging mechanical properties change with age, leading to biological, functional and health-related consequences. Despite extensive literature on skin aging, only very limited quantitative data are available on microstructural changes and the corresponding macroscopic biomechanical behavior as they evolve over time. This work provides a wide-range multiscale mechanical characterization of skin of newborn, adult and aged mice, and quantifies microstructural correlations in tissue morphology, collagen content, organization and cross-linking. Remarkably, aged skin retained normal hydration and normal biomechanical function in the physiological loading range but showed significantly reduced properties at super-physiological loading. Our data show that age-related microstructural differences have a profound effect not only on tissue-level properties but also on the cell-level biophysical environment., 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 molecular mechanisms of progressive right heart failure are incompletely understood. In this study, we systematically examined transcriptomic changes occurring over months in isolated cardiomyocytes or whole heart tissues from failing right and left ventricles in rat models of pulmonary artery banding (PAB) or aortic banding (AOB). Detailed bioinformatics analyses resulted in the identification of gene signature, protein and transcription factor networks specific to ventricles and compensated or decompensated disease states. Proteomic and RNA-FISH analyses confirmed PAB-mediated regulation of key genes and revealed spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with transcriptome datasets from human patients with chronic thromboembolic pulmonary hypertension (CTEPH) led to the identification of more than 50 genes whose expression levels correlated with the severity of right heart disease, including multiple matrix-regulating and secreted factors. These data define a conserved, differentially regulated genetic network associated with right heart failure in rats and humans., (© 2024. The Author(s).)

Rationale and Objectives: To compare a conventional T1 volumetric interpolated breath-hold examination (VIBE) with SPectral Attenuated Inversion Recovery (SPAIR) fat saturation and a deep learning (DL)-reconstructed accelerated VIBE sequence with SPAIR fat saturation achieving a 50 % reduction in breath-hold duration (hereafter, VIBE-SPAIR DL ) in terms of image quality and diagnostic confidence., Materials and Methods: This prospective study enrolled consecutive patients referred for upper abdominal MRI from November 2023 to December 2023 at a single tertiary center. Patients underwent upper abdominal MRI with acquisition of non-contrast and gadobutrol-enhanced conventional VIBE-SPAIR (fourfold acceleration, acquisition time 16 s) and VIBE-SPAIR DL (sixfold acceleration, acquisition time 8 s) on a 1.5 T scanner. Image analysis was performed by four readers, evaluating homogeneity of fat suppression, perceived signal-to-noise ratio (SNR), edge sharpness, artifact level, lesion detectability and diagnostic confidence. A statistical power analysis for patient sample size estimation was performed. Image quality parameters were compared by a repeated measures analysis of variance, and interreader agreement was assessed using Fleiss' κ., Results: Among 450 consecutive patients, 45 patients were evaluated (mean age, 60 years ± 15 [SD]; 27 men, 18 women). VIBE-SPAIR DL acquisition demonstrated superior SNR (P < 0.001), edge sharpness (P < 0.001), and reduced artifacts (P < 0.001) with substantial to almost perfect interreader agreement for non-contrast (κ: 0.70-0.91) and gadobutrol-enhanced MRI (κ: 0.68-0.87). No evidence of a difference was found between conventional VIBE-SPAIR and VIBE-SPAIR DL regarding homogeneity of fat suppression, lesion detectability, or diagnostic confidence (all P > 0.05)., Conclusion: Deep learning reconstruction of VIBE-SPAIR facilitated a reduction of breath-hold duration by half, while reducing artifacts and improving image quality., Summary: Deep learning reconstruction of prospectively accelerated T1 volumetric interpolated breath-hold examination for upper abdominal MRI enabled a 50 % reduction in breath-hold time with superior image quality., Key Results: 1) In a prospective analysis of 45 patients referred for upper abdominal MRI, accelerated deep learning (DL)-reconstructed VIBE images with spectral fat saturation (SPAIR) showed better overall image quality, with better perceived signal-to-noise ratio and less artifacts (all P < 0.001), despite a 50 % reduction in acquisition time compared to conventional VIBE. 2) No evidence of a difference was found between conventional VIBE-SPAIR and accelerated VIBE-SPAIR DL regarding lesion detectability or diagnostic confidence., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dominik Nickel reports a relationship with Siemens Healthineers that includes: employment. The other 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 Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

From 2025, Health Technology Developers (HTDs) have to submit EU HTA dossiers. The joint clinical assessment (JCA) aims to streamline HTA processes and access to medicinal products across Europe. Currently, German HTA bodies IQWiG and G-BA actively shape the JCA methodology. Here we examine if German HTA dossier requirements are suitable for the JCA. We compare the number of safety endpoint and subgroup analyses in German dossiers with analyses considered in IQWIG's benefit assessment and evaluate if these analyses were considered by the G-BA. We further investigated how the number of analyses was affected by the latest change in the German dossier template. With the current template, HTDs report in median 2.6 times more analyses on adverse events (AE) and 1.1 times more subgroup categories than in the previous template. IQWiG does not consider 33% of AE analyses and 73% of the subgroup categories presented by the HTD under the current template. G-BA considered the same AE as IQWiG in 76% of cases. Subgroups were uncommented by G-BA in most cases, independent of the template (previous: 93%, current 85%) and unconsidered in the conclusion on additional benefit (previous: 77%, current 69%). Thus, changes in the dossier template drastically increased HTD workload, but additional analyses seem unconsidered by the HTA bodies. With a broader scope in JCA, this effect could be amplified. To mitigate duplicative efforts and ensure prompt availability of medicinal products as envisioned by the HTAR, we suggest well-chosen and precise dossier requirements, early consultations, and early HTD engagement., (© 2023. The Author(s).)

While the elucidation of regulatory mechanisms of folded proteins is facilitated due to their amenability to high-resolution structural characterization, investigation of these mechanisms in disordered proteins is more challenging due to their structural heterogeneity, which can be captured by a variety of biophysical approaches. Here, we used the transcriptional master corepressor CtBP, which binds the putative metastasis suppressor RAI2 through repetitive SLiMs, as a model system. Using cryo-electron microscopy embedded in an integrative structural biology approach, we show that RAI2 unexpectedly induces CtBP polymerization through filaments of stacked tetrameric CtBP layers. These filaments lead to RAI2-mediated CtBP nuclear foci and relieve its corepressor function in RAI2-expressing cancer cells. The impact of RAI2-mediated CtBP loss-of-function is illustrated by the analysis of a diverse cohort of prostate cancer patients, which reveals a substantial decrease in RAI2 in advanced treatment-resistant cancer subtypes. As RAI2-like SLiM motifs are found in a wide range of organisms, including pathogenic viruses, our findings serve as a paradigm for diverse functional effects through multivalent interaction-mediated polymerization by disordered proteins in healthy and diseased conditions., (© 2024. The Author(s).)

Purpose: To assess the diagnostic accuracy of ChatGPT-4V in interpreting a set of four chest CT slices for each case of COVID-19, non-small cell lung cancer (NSCLC), and control cases, thereby evaluating its potential as an AI tool in radiological diagnostics., Materials and Methods: In this retrospective study, 60 CT scans from The Cancer Imaging Archive, covering COVID-19, NSCLC, and control cases were analyzed using ChatGPT-4V. A radiologist selected four CT slices from each scan for evaluation. ChatGPT-4V's interpretations were compared against the gold standard diagnoses and assessed by two radiologists. Statistical analyses focused on accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), along with an examination of the impact of pathology location and lobe involvement., Results: ChatGPT-4V showed an overall diagnostic accuracy of 56.76%. For NSCLC, sensitivity was 27.27% and specificity was 60.47%. In COVID-19 detection, sensitivity was 13.64% and specificity of 64.29%. For control cases, the sensitivity was 31.82%, with a specificity of 95.24%. The highest sensitivity (83.33%) was observed in cases involving all lung lobes. The chi-squared statistical analysis indicated significant differences in Sensitivity across categories and in relation to the location and lobar involvement of pathologies., Conclusion: ChatGPT-4V demonstrated variable diagnostic performance in chest CT interpretation, with notable proficiency in specific scenarios. This underscores the challenges of cross-modal AI models like ChatGPT-4V in radiology, pointing toward significant areas for improvement to ensure dependability. The study emphasizes the importance of enhancing these models for broader, more reliable medical use., (© 2024. The Author(s).)

Zoonoses such as ZIKV and SARS-CoV-2 pose a severe risk to global health. There is urgent need for broad antiviral strategies based on host-targets filling gaps between pathogen emergence and availability of therapeutic or preventive strategies. Significant reduction of pathogen titers decreases spread of infections and thereby ensures health systems not being overloaded and public life to continue. Based on previously observed interference with FGFR1/2-signaling dependent impact on interferon stimulated gene (ISG)-expression, we identified Pim kinases as promising druggable cellular target. We therefore focused on analyzing the potential of pan-Pim kinase inhibition to trigger a broad antiviral response. The pan-Pim kinase inhibitor AZD1208 exerted an extraordinarily high antiviral effect against various ZIKV isolates, SARS-CoV-2 and HBV. This was reflected by strong reduction in viral RNA, proteins and released infectious particles. Especially in case of SARS-CoV-2, AZD1208 led to a complete removal of viral traces in cells. Kinome-analysis revealed vast changes in kinase landscape upon AZD1208 treatment, especially for inflammation and the PI3K/Akt-pathway. For ZIKV, a clear correlation between antiviral effect and increase in ISG-expression was observed. Based on a cell culture model with impaired ISG-induction, activation of the PI3K-Akt-mTOR axis, leading to major changes in the endolysosomal equilibrium, was identified as second pillar of the antiviral effect triggered by AZD1208-dependent Pim kinase inhibition, also against HBV. We identified Pim-kinases as cellular target for a broad antiviral activity. The antiviral effect exerted by inhibition of Pim kinases is based on at least two pillars: innate immunity and modulation of the endolysosomal system., 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.)

Patient-tailored silicone plug for HeartMate 3™ left ventricular assist device explantation in two successive males proceeded successfully. Given medical therapeutic advancements, FDA-approved plug systems designed by LVAD manufacturers themselves will be necessary for the near future to provide a safe and simple device explantation alternative that fulfills all regulatory standards., (© 2023. The Author(s).)

Purpose: Supported decision-making (SDM) is an emerging and innovative alternative to substitute decision-making practices. While relationships are pivotal in establishing proper and effective SDM, scant research has examined these relationships in-depth. This study explores how decision-making supporters perceive relationships embedded in SDM for adults with disabilities. Furthermore, it compares the points of view of family and volunteer supporters on these relationships., Materials and Methods: Using a semi-structured interview guide, in-depth interviews were held with 16 family and 16 volunteer supporters of Israeli decision-makers with disabilities., Results: Both family and volunteer supporters addressed the centrality of the support relationship. However, they differed in their perspectives on the ways such relationships should be formed and on their boundaries. We distinguish between families' continuing relationships vs. volunteers' emerging relationships to emphasize the identified differences., Conclusions: The findings highlighted the importance of relationships to SDM processes, highlighting the need to examine in greater depth whether and how "typical" family relationships differ from SDM relationships. Based on these findings, we recommend training and guidance for both family and volunteer supporters in developing and strengthening these relationships.

Background: A structural reform of the German psychotherapy guideline in 2017 was intended to facilitate access to outpatient guideline psychotherapy. In the present study, we evaluate the effects of this reform in particular for patients with a comorbidity of mental disorders and chronic physical conditions (cMP)., Methods: Pre-post analyses of the two primary endpoints "percentage of mentally ill persons who have made an initial contact with a psychotherapist" and "waiting time for guideline psychotherapy" were carried out employing population-based and weighted routine statutory health insurance data from the German BARMER. The secondary endpoints included evaluations from the patients' perspective, based on a representative survey of patients in psychotherapy, and an overview of the health care situation based on data from the National Association of Statutory Health Insurance Physicians (Kassenärztliche Bundesvereinigung, KBV) (study registration number: DRKS00020344)., Results: From 2015 to 2018, the percentage of mentally ill persons who had made an initial contact with a psychotherapist rose moderately, from 3.7% (95% confidence interval, [3.6; 3.7]) to 3.9% [3.8; 3.9] among persons with cMP and from 7.3% [7.2; 7.4] to 7.6% [7.5; 7.7] among those with mental disorders but without any chronic physical condition (MnoP). The new structural elements were integrated into patient care. The interval of time between the initial contact and the beginning of guideline psychotherapy became longer in both groups, from a mean of 80.6 [79.4; 81.8] to 114.8 [113.4; 116.2] days among persons with complex disease and from 80.2 [79.2; 81.3] to 109.6 [108.4; 111.0] days among persons with non-complex disease; most patients considered the waiting time. Approximately 8% of the patients who sought psychotherapy reported that they had not obtained access to a psychotherapist., Conclusion: Neither in general nor for patients with cMP did the introduction of the structural reform appreciably lower the access barriers to psychotherapy. Further steps are needed so that outpatient care can meet the needs of all patients and particularly those with cMP.

Vitamin B 12 (cobalamin or Cbl) functions as a cofactor in two important enzymatic processes in human cells, and life is not sustainable without it. B 12 is obtained from food and travels from the stomach, through the intestine, and into the bloodstream by three B 12 -transporting proteins: salivary haptocorrin (HC), gastric intrinsic factor, and transcobalamin (TC), which all bind B 12 with high affinity and require proteolytic degradation to liberate Cbl. After intracellular delivery of dietary B 12 , Cbl in the aquo/hydroxocobalamin form can coordinate various nucleophiles, for example, GSH, giving rise to glutathionylcobalamin (GSCbl), a naturally occurring form of vitamin B 12 . Currently, there is no data showing whether GSCbl is recognized and transported in the human body. Our crystallographic data shows for the first time the complex between a vitamin B 12 transporter and GSCbl, which compared to aquo/hydroxocobalamin, binds TC equally well. Furthermore, sequence analysis and structural comparisons show that TC recognizes and transports GSCbl and that the residues involved are conserved among TCs from different organisms. Interestingly, haptocorrin and intrinsic factor are not structurally tailored to bind GSCbl. This study provides new insights into the interactions between TC and Cbl., Competing Interests: Conflict of interests The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: We evaluated the prognostic role of pre-salvage prostate-specific membrane antigen-radioguided surgery (PSMA-RGS) serum levels of alkaline phosphatase (AP), carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH), and neuron-specific enolase (NSE)., Materials and Methods: Patients who consecutively underwent PSMA-RGS for prostate cancer (PCa) oligorecurrence between January 2019 and January 2022 were selected. Biomarkers were assessed one day before surgery. Cox regression and logistic regression models tested the relationship between biochemical recurrence-free survival (BFS), 6- and 12-month biochemical recurrence (BCR), and several independent variables, including biomarkers., Results: 153 consecutive patients were analyzed. In the univariable Cox regression analysis, none of the biomarkers achieved predictor status (AP: hazard ratio [HR] = 1.03, 95% CI 0.99, 1.01; p = 0.19; CEA: HR = 1.73, 95% CI 0.94, 1.21; p = 0.34; LDH: HR = 1.01, 95% CI 1.00, 1.01; p = 0.05; NSE: HR = 1.02, 95% CI 0.98, 1.06; p = 0.39). The only independent predictor of BFS was the number of positive lesions on PSMA PET (HR = 1.17, 95% CI 1.02, 1.30; p = 0.03). The number of positive lesions was confirmed as independent predictor for BCR within 6 and 12 months (BCR < 6 months: odds ratio [OR] = 1.1, 95% CI 1.0, 1.3; p = 0.04; BCR < 12 months: OR = 1.1, 95% CI 1.0, 1.3; p = 0.04)., Conclusion: The assessment of AP, CEA, LDH, and NSE before salvage PSMA-RGS showed no prognostic impact. Further studies are needed to identify possible predictors that will optimize patient selection for salvage PSMA-RGS., (© 2024. The Author(s).)

Multiple metrics are used when assessing and validating the performance of quantitative structure-activity relationship (QSAR) models. In the case of binary classification, balanced accuracy is a metric to assess the global performance of such models. In contrast to accuracy, balanced accuracy does not depend on the respective prevalence of the two categories in the test set that is used to validate a QSAR classifier. As such, balanced accuracy is used to overcome the effect of imbalanced test sets on the model's perceived accuracy. Matthews' correlation coefficient (MCC), an alternative global performance metric, is also known to mitigate the imbalance of the test set. However, in contrast to the balanced accuracy, MCC remains dependent on the respective prevalence of the predicted categories. For simplicity, the rest of this work is based on the positive prevalence. The MCC value may be underestimated at high or extremely low positive prevalence. It contributes to more challenging comparisons between experiments using test sets with different positive prevalences and may lead to incorrect interpretations. The concept of balanced metrics beyond balanced accuracy is, to the best of our knowledge, not yet described in the cheminformatic literature. Therefore, after describing the relevant literature, this manuscript will first formally define a confusion matrix, sensitivity and specificity and then present, with synthetic data, the danger of comparing performance metrics under nonconstant prevalence. Second, it will demonstrate that balanced accuracy is the performance metric accuracy calibrated to a test set with a positive prevalence of 50% (i.e., balanced test set). This concept of balanced accuracy will then be extended to the MCC after showing its dependency on the positive prevalence. Applying the same concept to any other performance metric and widening it to the concept of calibrated metrics will then be briefly discussed. We will show that, like balanced accuracy, any balanced performance metric may be expressed as a function of the well-known values of sensitivity and specificity. Finally, a tale of two MCCs will exemplify the use of this concept of balanced MCC versus MCC with four use cases using synthetic data. SCIENTIFIC CONTRIBUTION: This work provides a formal, unified framework for understanding prevalence dependence in model validation metrics, deriving balanced metric expressions beyond balanced accuracy, and demonstrating their practical utility for common use cases. In contrast to prior literature, it introduces the derived confusion matrix to express metrics as functions of sensitivity, specificity and prevalence without needing additional coefficients. The manuscript extends the concept of balanced metrics to Matthews' correlation coefficient and other widely used performance indicators, enabling robust comparisons under prevalence shifts., (© 2024. The Author(s).)

Background: Metastasis is the leading cause of cancer-related death in non-small cell lung cancer (NSCLC) patients. We previously showed that low HERC5 expression predicts early tumor dissemination and a dismal prognosis in NSCLC patients. Here, we performed functional studies to unravel the mechanism underlying the "metastasis-suppressor" effect of HERC5, with a focus on mitochondrial metabolism pathways., Methods: We assessed cell proliferation, colony formation potential, anchorage-independent growth, migration, and wound healing in NSCLC cell line models with HERC5 overexpression (OE) or knockout (KO). To study early tumor cell dissemination, we used these cell line models in zebrafish experiments and performed intracardial injections in nude mice. Mass spectrometry (MS) was used to analyze protein changes in whole-cell extracts. Furthermore, electron microscopy (EM) imaging, cellular respiration, glycolytic activity, and lactate production were used to investigate the relationships with mitochondrial energy metabolism pathways., Results: Using different in vitro NSCLC cell line models, we showed that NSCLC cells with low HERC5 expression had increased malignant and invasive properties. Furthermore, two different in vivo models in zebrafish and a xenograft mouse model showed increased dissemination and metastasis formation (in particular in the brain). Functional enrichment clustering of MS data revealed an increase in mitochondrial proteins in vitro when HERC5 levels were high. Loss of HERC5 leads to an increased Warburg effect, leading to improved adaptation and survival under prolonged inhibition of oxidative phosphorylation., Conclusions: Taken together, these results indicate that low HERC5 expression increases the metastatic potential of NSCLC in vitro and in vivo. Furthermore, HERC5-induced proteomic changes influence mitochondrial pathways, ultimately leading to alterations in energy metabolism and demonstrating its role as a new potential metastasis suppressor gene., (© 2024. The Author(s).)

Chloride channel accessory 2 (CLCA2) is a transmembrane protein, which promotes adhesion of keratinocytes and their survival in response to hyperosmotic stress. Here we show that CLCA2 is transported to the nucleus of keratinocytes via extracellular vesicles. The nuclear localization is functionally relevant, since wild-type CLCA2, but not a mutant lacking the nuclear localization signal, suppressed migration of keratinocytes and protected them from hyperosmotic stress-induced cell death. In the nucleus, CLCA2 bound to and activated β-catenin, resulting in enhanced expression of Wnt target genes. Mass-spectrometry-based interaction screening and functional rescue studies identified RNA binding protein 3 as a key effector of nuclear CLCA2. This is of likely relevance in vivo because both proteins co-localize in the human epidermis. Together, these results identify an unexpected nuclear function of CLCA2 in keratinocytes under homeostatic and stress conditions and suggest a role of extracellular vesicles and their nuclear transport in the control of key cellular activities., (© 2024 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Tissue repair and fibrosis involve the dynamic remodeling of collagen, and accurate detection of these sites is of utmost importance. Here, we use a collagen peptide sensor (1) to visualize collagen formation and remodeling during wound healing in mice and humans. We show that the probe binds selectively to sites of collagen formation and remodeling at different stages of healing. Compared to conventional methods, the peptide sensor localizes preferentially to areas of collagen synthesis and remodeling at the wound edge and not in matured fibrillar collagen. We also demonstrate its applicability for in vivo wound imaging and for discerning differential remodeling in wounds of transgenic mice with altered collagen dynamics. Our findings show the value of 1 as a diagnostic tool to rapidly identify the sites of matrix remodeling in tissue sections, which will aid in the conception of new therapeutic strategies for fibrotic disorders and defective tissue repair., Competing Interests: Declaration of competing interest The authors have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

During starvation in the yeast Saccharomyces cerevisiae vacuolar vesicles fuse and lipid droplets (LDs) can become internalized into the vacuole in an autophagic process named lipophagy. There is a lack of tools to quantitatively assess starvation-induced vacuole fusion and lipophagy in intact cells with high resolution and throughput. Here, we combine soft X-ray tomography (SXT) with fluorescence microscopy and use a deep-learning computational approach to visualize and quantify these processes in yeast. We focus on yeast homologs of mammalian NPC1 (NPC intracellular cholesterol transporter 1; Ncr1 in yeast) and NPC2 proteins, whose dysfunction leads to Niemann Pick type C (NPC) disease in humans. We developed a convolutional neural network (CNN) model which classifies fully fused versus partially fused vacuoles based on fluorescence images of stained cells. This CNN, named Deep Yeast Fusion Network (DYFNet), revealed that cells lacking Ncr1 ( ncr1∆ cells) or Npc2 ( npc2∆ cells) have a reduced capacity for vacuole fusion. Using a second CNN model, we implemented a pipeline named LipoSeg to perform automated instance segmentation of LDs and vacuoles from high-resolution reconstructions of X-ray tomograms. From that, we obtained 3D renderings of LDs inside and outside of the vacuole in a fully automated manner and additionally measured droplet volume, number, and distribution. We find that ncr1∆ and npc2∆ cells could ingest LDs into vacuoles normally but showed compromised degradation of LDs and accumulation of lipid vesicles inside vacuoles. Our new method is versatile and allows for analysis of vacuole fusion, droplet size and lipophagy in intact cells. Abbreviations: BODIPY493/503: 4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza- s -Indacene; BPS: bathophenanthrolinedisulfonic acid disodium salt hydrate; CNN: convolutional neural network; DHE; dehydroergosterol; npc2∆ , yeast deficient in Npc2; DSC, Dice similarity coefficient; EM, electron microscopy; EVs, extracellular vesicles; FIB-SEM, focused ion beam milling-scanning electron microscopy; FM 4-64, N -(3-triethylammoniumpropyl)-4-(6-[4-{diethylamino} phenyl] hexatrienyl)-pyridinium dibromide; LDs, lipid droplets; Ncr1, yeast homolog of human NPC1 protein; ncr1∆ , yeast deficient in Ncr1; NPC, Niemann Pick type C; NPC2, Niemann Pick type C homolog; OD 600 , optical density at 600 nm; ReLU, rectifier linear unit; PPV, positive predictive value; NPV, negative predictive value; MCC, Matthews correlation coefficient; SXT, soft X-ray tomography; UV, ultraviolet; YPD, yeast extract peptone dextrose.

Abstract: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who have a history of severe and frequent bleeds. However, data from prospective studies are scarce. WIL-31, a prospective, noncontrolled, international phase 3 trial, investigated the efficacy and safety of Wilate prophylaxis in severe patients with VWD. Male and female patients 6 years or older with VWD types 1, 2 (except 2N), or 3 who had completed a prospective, 6-month, on-demand, run-in study (WIL-29) were eligible to receive Wilate prophylaxis for 12 months. At baseline, patients (n = 33) had a median age of 18 years. Six (18%) patients had severe type 1, 5 (15%) had type 2, and 22 (67%) had type 3 VWD. The primary end point of a >50% reduction in mean total annualized bleeding rate (TABR) with Wilate prophylaxis vs prior on-demand treatment was met; mean TABR during prophylaxis was 5.2, representing an 84.4% reduction. The bleeding reduction was consistent across age, sex, and VWD types. The mean spontaneous ABR was 3.2, representing an 86.9% reduction vs on-demand treatment. During prophylaxis, 10 (30.3%) patients had 0 bleeding events and 15 (45.5%) patients had 0 spontaneous bleeding events. Of 173 BEs, 84.4% were minor and 69.9% treated. No serious adverse events related to study treatment and no thrombotic events were recorded. Overall, WIL-31 showed that Wilate prophylaxis was efficacious and well-tolerated in pediatric and adult patients with VWD of all types. The WIL-29 and WIL-31 trials were registered at www.ClinicalTrials.gov as #NCT04053699 and #NCT04052698, respectively., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In this study, a novel application of synchrotron X-ray nanotomography based on high-resolution full-field transmission X-ray microscopy for characterizing the structure and morphology of micrometric hollow polymeric fibers is presented. By employing postimage analysis using an open-source software such as Tomviz and ImageJ, various key parameters in fiber morphology, including diameter, wall thickness, wall thickness distribution, pore size, porosity, and surface roughness, were assessed. Electrospun polycaprolactone fibers with micrometric diameters and submicrometric features with induced porosity via gas dissolution foaming were used to this aim. The acquired synchrotron X-ray nanotomography data were analyzed using two approaches: 3D tomographic reconstruction and 2D radiographic projection-based analysis. The results of the combination of both approaches demonstrate unique capabilities of this technique, not achievable by other available techniques, allowing for a full characterization of the internal and external morphology and structure of the fibers as well as to obtain valuable qualitative insights into the overall fiber structure., Competing Interests: Conflict of Interest The authors declare that they have no competing interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Microscopy Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

On September 18, 2023, Cancer Support Community convened patient and caregiver advocates, health care providers, policy experts, and health care innovators and thought leaders for a roundtable discussion on the need to ensure that patients, people with disabilities, and caregivers have a voice in defining "clinical benefit" for the purpose of Medicare Part D drug price negotiations and future health care policies that impact patients. The meeting featured presentations from Lara Strawbridge, Deputy Director for Policy at the Medicare Drug Rebate and Negotiations Group in the Center for Medicare, regulatory expert, Dr Monique Nolan, Counsel at Arnold and Porter, LLP, and 3 panel discussions: IRA Implementation-What Matters to Patients, a discussion of policies expected to impact patients and caregivers who are likely to rely heavily on high-cost drugs or biologics to treat cancer or other chronic illnesses, as well as the future development of novel therapies; The Science of Measuring Patient Experience, a discussion of current science of measuring patient experience and how it should be incorporated into the definition of clinical benefit; and Developing an Infrastructure for External Feedback, a discussion of actions and goals for patient engagement, advocacy opportunities, and how to best coordinate such efforts. This article represents an analysis of relevant resources as well as highlights from these sessions and subsequent discussions. It also outlines principles for engaging patient and provider advocacy organizations, whether in policy, media, or online discussions, surrounding the implementation of the Medicare Drug Price Negotiation Program.

Ciliary defects cause several ciliopathies, some of which have late onset, suggesting cilia are actively maintained. Still, we have a poor understanding of the mechanisms underlying their maintenance. Here, we show Drosophila melanogaste r IFT88 ( Dm IFT88/nompB) continues to move along fully formed sensory cilia. We further identify Inactive, a TRPV channel subunit involved in Drosophila hearing and negative-gravitaxis behaviour, and a yet uncharacterised Drosophila Guanylyl Cyclase 2d ( Dm Gucy2d/CG34357) as Dm IFT88 cargoes. We also show Dm IFT88 binding to the cyclase´s intracellular part, which is evolutionarily conserved and mutated in several degenerative retinal diseases, is important for the ciliary localisation of Dm Gucy2d. Finally, acute knockdown of both Dm IFT88 and Dm Gucy2d in ciliated neurons of adult flies caused defects in the maintenance of cilium function, impairing hearing and negative-gravitaxis behaviour, but did not significantly affect ciliary ultrastructure. We conclude that the sensory ciliary function underlying hearing in the adult fly requires an active maintenance program which involves Dm IFT88 and at least two of its signalling transmembrane cargoes, Dm Gucy2d and Inactive., (© 2024 Werner et al.)

Abuse of amphetamine-type stimulants is linked to cardiovascular adverse effects like arrhythmias, accelerated atherosclerosis, acute coronary syndromes and sudden cardiac death. Excessive catecholamine release following amphetamine use causes vasoconstriction and vasospasms, over time leading to hypertension, endothelial dysfunction or even cardiotoxicity. However, immediate vascular pathomechanisms related to amphetamine exposure, especially endothelial function, remain incompletely understood and were analyzed in this study. Pharmaco-pathological effects of acute d-amphetamine-sulfate (DAM) were investigated ex vivo using contraction-force measurements of rat carotid artery rings and in vitro using label-free, real-time electrochemical impedance spectroscopy (EIS) on endothelial and smooth muscle cells. Specific receptor and target blocking was used to identify molecular targets and to characterize intracellular signaling. DAM induced vasodilation represented by 29.3±2.5% decrease in vascular tone (p<0.001) involving vascular endothelial growth factor receptor (VEGF-R) and protease activated receptor 1 (PAR-1). EIS revealed that DAM induces endothelial barrier disruption (-75.9±1.1% of initial cellular impedance, p<0.001) also involving VEGF-R and PAR-1. Further, in response to DAM, Rho-associated protein kinase (ROCK) mediated reversible contraction of actin cytoskeleton resulting in endothelial barrier disruption. Dephosphorylation of Serine1177 (-50.8±3.7%, p<0.001) and Threonine495 (-44.8±6.5%, p=0.0103) of the endothelial NO synthase (eNOS) were also observed. Blocking of VEGF-R and PAR-1 restored baseline eNOS Threonine495 phosphorylation. DAM induced vasodilation, enhanced vascular permeability and actin cytoskeleton contraction and induced eNOS hypophosphorylation involving VEGF-R, PAR-1 and ROCK. These results may contribute to a better understanding of severe adverse cardiovascular effects in amphetamine abuse., (© 2024. The Author(s).)

Background: Chemicals are not required to be tested systematically for their neurotoxic potency, although they may contribute to the development of several neurological diseases. The absence of systematic testing may be partially explained by the current Organisation for Economic Co-operation and Development (OECD) Test Guidelines, which rely on animal experiments that are expensive, laborious, and ethically debatable. Therefore, it is important to understand the risks to exposed workers and the general population exposed to domestic products. In this study, we propose a strategy to test the neurotoxicity of solvents using the commonly used glycol ethers as a case study., Objective: This study aims to provide a strategy that can be used by regulatory agencies and industries to rank solvents according to their neurotoxicity and demonstrate the use of toxicokinetic modeling to predict air concentrations of solvents that are below the no observed adverse effect concentrations (NOAECs) for human neurotoxicity determined in in vitro assays., Methods: The proposed strategy focuses on a complex 3D in vitro brain model (BrainSpheres) derived from human-induced pluripotent stem cells (hiPSCs). This model is accompanied by in vivo, in vitro, and in silico models for the blood-brain barrier (BBB) and in vitro models for liver metabolism. The data are integrated into a toxicokinetic model. Internal concentrations predicted using this toxicokinetic model are compared with the results from in vivo human-controlled exposure experiments for model validation. The toxicokinetic model is then used in reverse dosimetry to predict air concentrations, leading to brain concentrations lower than the NOAECs determined in the hiPSC-derived 3D brain model. These predictions will contribute to the protection of exposed workers and the general population with domestic exposures., Results: The Swiss Centre for Applied Human Toxicology funded the project, commencing in January 2021. The Human Ethics Committee approval was obtained on November 16, 2022. Zebrafish experiments and in vitro methods started in February 2021, whereas recruitment of human volunteers started in 2022 after the COVID-19 pandemic-related restrictions were lifted. We anticipate that we will be able to provide a neurotoxicity testing strategy by 2026 and predicted air concentrations for 6 commonly used propylene glycol ethers based on toxicokinetic models incorporating liver metabolism, BBB leakage parameters, and brain toxicity., Conclusions: This study will be of great interest to regulatory agencies and chemical industries needing and seeking novel solutions to develop human chemical risk assessments. It will contribute to protecting human health from the deleterious effects of environmental chemicals., International Registered Report Identifier (irrid): DERR1-10.2196/50300., (©Nancy B Hopf, Laura Suter-Dick, Jörg Huwyler, Myriam Borgatta, Lucie Hegg, David Pamies, Hélène Paschoud, Ramya Deepthi Puligilla, Elena Reale, Sophie Werner, Marie-Gabrielle Zurich. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 18.01.2024.)

Human skin equivalents (HSEs) serve as important tools for mechanistic studies with human skin cells, drug discovery, pre-clinical applications in the field of tissue engineering and for skin transplantation on skin defects. Besides the cellular and extracellular matrix (ECM) components used for HSEs, physical constraints applied on the scaffold during HSEs maturation influence tissue organization, functionality, and homogeneity. In this study, we introduce a 3D-printed culture insert that exposes bi-layered HSEs to a static radial constraint through matrix adhesion. We examine the effect of various diameters of the ring-shaped culture insert on the HSE's characteristics and compare them to state-of-the-art unconstrained and planar constrained HSEs. We show that radial matrix constraint of HSEs regulates tissue contraction, promotes fibroblast and matrix organization that is similar to human skin in vivo and improves keratinocyte differentiation, epidermal stratification, and basement membrane formation depending on the culture insert diameter. Together, these data demonstrate that the degree of HSE's contraction is an important design consideration in skin tissue engineering. Therefore, this study can help to mimic various in vivo skin conditions and to increase the control of relevant tissue properties., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: People with intellectual disabilities have the right to live in the community. As social workers have an important role in decisions regarding residential settings, this study examined their recommendations regarding residential living arrangements of individuals with intellectual disabilities., Method: Using a factorial survey approach 174 social workers were presented with true-to-life vignettes and asked to provide their recommendations regarding housing in community apartments, hostels (large group homes) and meonot (large institutions)., Results: Higher likelihood of recommending housing in a community apartment was associated with mild intellectual disability, lack of daily support needs, no sexual abuse history, and stated preference for a community apartment. Social workers' experience in working in a specific residential setting was associated with recommending it., Conclusions: Ongoing training on rights-based ethics and the importance of community inclusion should be provided to social workers. Further, community alternatives should be made available to all individuals with disabilities., (© 2023 The Authors. Journal of Applied Research in Intellectual Disabilities published by John Wiley & Sons Ltd.)