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Abstract Phishers exploit the social nature of social media, thereby targeting young adults, who are highly susceptible to phishing. This study focuses on two under-researched factors influencing young adults’ susceptibility to social media phishing: the user’s relation to the message sender and Fear of Missing Out (FoMO). In an online vignette study, 193 young adults were presented with Instagram chat messages from either known or unknown senders, accompanied by varying consequences for not clicking. These ranged from missing an event with no other user (no consequences) to missing an event with one (low) or several other users (high consequences). The analysis focused on intended behaviour and suspicion, while also capturing young adults’ situational fear of missing out on the scenario-based event with the message sender (State FoMO) and their individual Trait FoMO. The results highlight that the user-sender relation is a strong predictor of phishing susceptibility and a crucial contributor to State FoMO. Furthermore, young adults who are high in Trait FoMO exhibited lower suspicion towards phishing attempts. These findings are discussed along with methodological considerations. In addition, strategies to mitigate the identified vulnerabilities are suggested, focusing on areas where social media phishing is most likely to affect young adults.

Abstract The crosstalk between cancer and stromal cells plays a critical role in tumor progression. Syntenin is a small scaffold protein involved in the regulation of intercellular communication that is emerging as a target for cancer therapy. Here, we show that certain aggressive forms of acute myeloid leukemia (AML) reduce the expression of syntenin in bone marrow stromal cells (BMSC). Stromal syntenin deficiency, in turn, generates a pro‐tumoral microenvironment. From serial transplantations in mice and co‐culture experiments, we conclude that syntenin‐deficient BMSC stimulate AML aggressiveness by promoting AML cell survival and protein synthesis. This pro‐tumoral activity is supported by increased expression of endoglin, a classical marker of BMSC, which in trans stimulates AML translational activity. In short, our study reveals a vicious signaling loop potentially at the heart of AML–stroma crosstalk and unsuspected tumor‐suppressive effects of syntenin that need to be considered during systemic targeting of syntenin in cancer therapy.

Abstract Small‐cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC‐driven non‐neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high‐throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First‐in‐class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S‐phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC‐driven non‐neuroendocrine tumors which are resistant to first‐line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin–berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.

Abstract Multi‐omics analyses are used in microbiome studies to understand molecular changes in microbial communities exposed to different conditions. However, it is not always clear how much each omics data type contributes to our understanding and whether they are concordant with each other. Here, we map the molecular response of a synthetic community of 32 human gut bacteria to three non‐antibiotic drugs by using five omics layers (16S rRNA gene profiling, metagenomics, metatranscriptomics, metaproteomics and metabolomics). We find that all the omics methods with species resolution are highly consistent in estimating relative species abundances. Furthermore, different omics methods complement each other for capturing functional changes. For example, while nearly all the omics data types captured that the antipsychotic drug chlorpromazine selectively inhibits Bacteroidota representatives in the community, the metatranscriptome and metaproteome suggested that the drug induces stress responses related to protein quality control. Metabolomics revealed a decrease in oligosaccharide uptake, likely caused by Bacteroidota depletion. Our study highlights how multi‐omics datasets can be utilized to reveal complex molecular responses to external perturbations in microbial communities.

The Skagerrak is the main depot center for organic matter and anthropogenic pollutants from the entire North Sea. Changes in ocean circulation or suspended matter supply might impact the sediment redox conditions. Indeed, little is known about the response of Skagerrak sediment and associated pollutants to different oxygen levels. We investigated sediments from three stations within the Skagerrak and incubated them for up to twelve months under aerobic and anaerobic conditions. Furthermore, we present the first δ98/95Mo data for Skagerrak sediment profiles and the incubations to be utilized as a redox tracer. The sediment profiles of metals reflected anthropogenic pollution (Cu, Ni, Pb) but differed regionally with redox conditions. We differentiated redox conditions mainly by sediment and porewater Fe, Mn, Mo and δ98/95Mo. In aerobic incubations, no Mn or Fe reduction was detected, while under anaerobic conditions, initial Mn and Fe reduction decreased after approximately three months. Under anaerobic conditions, a strong isotopic fractionation of Mo in the dissolved phase was found, reaching up to 5.03 ± 0.10‰, probably caused by incomplete thiolation of molybdate under low hydrogen sulfide levels. During the incubations, Cd, Cu, Ni, Pb were mobilized. While Cu and Cd were mobilized under aerobic conditions, Ni and Pb mobilization depended mainly on remineralization and redox conditions. Our results show that changes in oxygen conditions in the Skagerrak can have significant effects on the (legacy) metals stored in the sediment over the past decades. [ABSTRACT FROM AUTHOR]

Airway management in children poses unique challenges due to the different anatomy, physiology, and pathophysiology across the pediatric age span. The recently published joint European Society of Anaesthesiology and Intensive Care-British Journal of Anaesthesia (ESAIC-BJA) neonatal and infant airway management guidelines provide recommendations and suggestions to support clinicians in deciding the best strategy. These guidelines represent a framework with the most recent and up-to-date evidence, from the initial assessment to the management of normal and difficult airways up to the extubation phase. However, such guidelines have intrinsic limitations due to the lack of supporting evidence in various fields of airway management. Pediatric institutions should adopt guidelines after careful internal review according to the local circumstances, including caseload, equipment and expertise. The current narrative review focused on providing references and practical tips on pediatric airway management, which is still not completely elucidated. Moreover, the authors put particular emphasis on the influence of human factors on the overall success of tracheal intubation, the incidence of complications, and the outcomes for patients. [ABSTRACT FROM AUTHOR]

The EU-protected butterfly Euphydryas aurinia inhabits oligotrophic grasslands in Western and Central Europe. In the Czech Republic, only 11 colonies inhabiting 23.6 ha were known prior to accession to the EU. Since then, targeted searches for occupied sites have increased the numbers to 97 sites/297.8 ha as of 2021, forming three metapopulation clusters in the western part of the country. Owing to efforts to secure legal conservation status and management for the sites, most of them are legally protected, and conservation mowing is the prevailing management at present. Annual larval web numbers monitoring revealed considerably lower densities and carrying capacity than in other E. aurinia studies, which we interpret by more generous delimitation of site boundaries. Larger and less fluctuating sites experienced fewer extinctions than smaller, more fluctuating sites. Grazing was associated with extinction of local populations, long-term neglect excluded long-term persistence, but effects of conservation mowing were ambiguous. Connectivity was the only predictor of recolonisation. Despite tenfold fluctuations in annual web numbers and losses of some sites, total web numbers have steadily increased over the past two decades, which we attribute to the positive effect of the vegetation management. The conservation efforts have been so far satisfactory, but increasing connectivity of the metapopulations is necessary in the long term. [ABSTRACT FROM AUTHOR]

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Copyright of Gefaesschirurgie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Integrating artificial intelligence (AI) into critical domains such as healthcare holds immense promise. Nevertheless, significant challenges must be addressed to avoid harm, promote the well-being of individuals and societies, and ensure ethically sound and socially just technology development. Innovative approaches like Embedded Ethics, which refers to integrating ethics and social science into technology development based on interdisciplinary collaboration, are emerging to address issues of bias, transparency, misrepresentation, and more. This paper aims to develop this approach further to enable future projects to effectively deploy it. Based on the practical experience of using ethics and social science methodology in interdisciplinary AI-related healthcare consortia, this paper presents several methods that have proven helpful for embedding ethical and social science analysis and inquiry. They include (1) stakeholder analyses, (2) literature reviews, (3) ethnographic approaches, (4) peer-to-peer interviews, (5) focus groups, (6) interviews with affected groups and external stakeholders, (7) bias analyses, (8) workshops, and (9) interdisciplinary results dissemination. We believe that applying Embedded Ethics offers a pathway to stimulate reflexivity, proactively anticipate social and ethical concerns, and foster interdisciplinary inquiry into such concerns at every stage of technology development. This approach can help shape responsible, inclusive, and ethically aware technology innovation in healthcare and beyond. [ABSTRACT FROM AUTHOR]

In cells, the term “cellular aging” represents a collection of biological changes that can precede the proliferative senescence states. Cells more resistant to proliferative senescence, such as the ones found in the basal layer of the epidermis, may also exhibit these aging patterns. Therefore, cellular aging events could be induced by endogenous signals named here as cellular aging triggers (CATs) components. The superoxide anion (O2⁻) could be a prime candidate for a CATs, as it is continuously produced by eukaryotic cells. To test this hypothesis, mitochondrial and cytoplasmic O2⁻ imbalances were induced in HaCaT keratinocytes using rotenone (ROT, 30 µM), which inhibits mitochondrial complex I and paraquat (PQT, 30 µM), which increases O2⁻ levels via redox cycling. ROT and PQT reduced cellular proliferation rate and elevated β-Galactosidase and transforming growth factor beta (TGF-β) levels. Furthermore, they increased the frequency of larger cells with nuclear alterations, the levels of oxidative markers, and interleukin 1β, a marker of the Senescence-Associated Secretory Phenotype (SASP). However, the mitochondrial O2⁻ imbalance caused by ROT led to more pronounced alterations compared to PQT. These findings support the hypothesis that the existence of CAT components, such as the O2⁻ anion, plays a significant role in cellular aging. [ABSTRACT FROM AUTHOR]

Purpose: Treatment strategies for space-occupying/symptomatic pineal cysts (PC) are still up for debate. In this study we present PC management, outcome data and risk factors for recurrence after surgery, focusing on microscopic/endoscopic procedures vs. stereotactic catheter implantation as alternative treatment concept to permanently drain PC into ventricles/cisterns. Methods: This monocentric retrospective analysis included clinical data from all consecutive PC patients treated surgically between 2000 and 2022. Postoperative neurological and functional outcomes, along with perioperative complications, as well as time to PC recurrence and MR-morphological data were evaluated. Results: 39 patients (median age 32.6 years, range: 5.1–71.6 years) were analyzed. Main presenting symptoms were headaches, visual impairment, and epileptic seizures. In 18 patients (46.2%) an enlarged ventricular system was preoperatively found with 7 patients (18.0%) suffering from occlusive hydrocephalus. 14 patients underwent microscopic/endosocopic surgery, in 25 cases stereotaxy was preferred. No complication was seen in the microsurgery/endoscopy group compared to one intracystic postoperative bleeding (2.6%) and two CSF leaks (5.1%) after stereotaxy (p = 0.5). Overall, clinical improvement and significant cyst volume reduction (p < 0.0001) was seen in all patients. Recurrent PC were seen in 23.1%, independent of surgical procedure (p = 0.2). In cases of recurrence, TTR was 25.2 ± 31.2 months. Male gender (p = 0.01), longer surgery time (p = 0.03) and preoperatively increased Evans index (EI) (p = 0.007) were significant risk factors for PC recurrence in multivariate analysis. Conclusion: In patients suffering from PC, microsurgical and stereotactic approaches can improve clinical symptoms at low procedural risk, with equal extent of volume reduction. However, preoperative ventricular enlargement and EI values should be considered for optimal treatment planning to reduce recurrence. [ABSTRACT FROM AUTHOR]

Edible insects have been proposed as a novel and sustainable source of protein and other essential nutrients for human consumption but nutrient absorption efficiency is still uncertain. We investigated zinc absorption from house crickets (Acheta domesticus) in a single-center and single-blinded cross-over study with children aged 24–36 months old in Kenya from September-November 2021. For this, children were randomized to consume two different experimental meals labeled with stable isotopes of zinc (Zn) at two different days, separated by a wash-out period of one month. Primary endpoints were the differences in amount of absorbed zinc (AZ) from maize-based meals enriched with intrinsically 67Zn-labeled house crickets (2.61 mg Zn, n = 28) in comparison with meals enriched with 68Zn (low-enriched: 0.90 mg Zn, n = 29); high-enriched: 3.24 mg Zn, n = 28) or with intrinsically 67Zn-labeled low-chitin cricket flour (2.51 mg Zn, n = 25), whereas the secondary endpoints were the differences in fractional zinc absorption. We found that AZ from meals with whole crickets (geometric mean: 0.36 mg; 95%CI: 0.30, 0.43) was 2.6 times higher than from low-enriched maize meals (0.14 mg; 0.11, 0.16; P < 0.001), while it was not different from low-chitin cricket flour meals. Absorbed zinc from both cricket meals was higher than that from high-enriched meals. No severe adverse side events were reported. We conclude that edible house crickets are a good source of well-absorbable zinc, and their increased consumption could contribute to the alleviation of zinc deficiency. This trial was registered at the Pan African Clinical Trials Registry as PACTR202104533831364. Zinc deficiency can impair child growth and development, and edible insects contain substantial amount of zinc. Here the authors report that edible house crickets are a source of well-absorbable zinc in a randomized crossover clinical trial in Kenyan children aged 24–36 months. [ABSTRACT FROM AUTHOR]

Diffraction-before-destruction imaging with ultrashort X-ray pulses can visualize non-equilibrium processes, such as chemical reactions, with sub-femtosecond precision in the native environment. Here, a nanospecimen diffracts a single X-ray flash before it disintegrates. The sample structure can be reconstructed from the coherent diffraction image (CDI). State-of-the-art X-ray snapshots lack high spatial resolution because of weak diffraction signal. Bleaching effects from photo-ionization significantly restrain image brightness scaling. We find that non-linear transient ion resonances can overcome this barrier if X-ray laser pulses are shorter than in most experiments. We compared snapshots from individual ≈ 100 nm Xe nanoparticles as a function of pulse duration and incoming X-ray fluence. Our experimental results and Monte Carlo simulations suggest that transient resonances can increase ionic scattering cross sections significantly beyond literature values. This provides a novel avenue towards substantial improvement of the spatial resolution in CDI in combination with sub-femtosecond temporal precision at the nanoscale. Diffraction-before-destruction of ultrashort X-ray pulses can visualize non-equilibrium processes at the nanoscale with sub-femtosecond precision. Here, the authors demonstrate how the brightness and the spatial resolution of such snapshots can be substantially increased despite ionization. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to assess the feasibility of transitioning from open to laparoscopic surgery for colorectal carcinoma in a primary care hospital setting. Despite the recognized benefits of laparoscopic surgery in postoperative recovery and its demonstrated oncological equivalence, only a minority of patients (30–40%) in Germany undergo laparoscopic procedures, primarily due to concerns which, in addition to the perioperative quality data and economic aspects, focus on patient safety. Methods: Over a three-year period (2012–2014), the transformation process was observed in a colorectal cancer center. Data from 237 patients (115 laparoscopic; 122 open) were collected prospectively and analyzed retrospectively. Short-term outcomes, including demographic data, perioperative complications, and quality metrics, as well as long-term survival data, were included. Results: Laparoscopic surgery demonstrated several advantages. Postoperative intensive care needs decreased significantly (average length of stay: laparoscopic 1.2 days vs. open 2.5 days; p = 0.032). Hospital stays were also shorter following laparoscopic surgery (median laparoscopic 10 days vs. median open 14 days; p = 0.011). Quality of specimens, particularly lymph node retrieval, remained comparable (median laparoscopic = 18 vs. median open = 19). Survival data showed non- inferiority of the laparoscopic approach. Despite higher initial costs, laparoscopic surgery yielded cost savings of approximately 3150 € per case due to reduced intensive care and shorter hospital stays. Conclusion: In conclusion, this study demonstrates the feasibility of transitioning from open to laparoscopic oncologic colorectal surgery in a primary care hospital setting. The findings suggest that such a transition can be accomplished without compromising the quality of specimens, while also realizing cost savings and maintaining patient safety. [ABSTRACT FROM AUTHOR]

Invasive infections with Aspergillus fumigatus in ICU patients are linked to high morbidity and mortality. Diagnosing invasive pulmonary aspergillosis (IPA) in non-immunosuppressed patients is difficult, as Aspergillus antigen (galactomannan [GM]) may have other causes. This retrospective study analyzed 160 ICU surgical patients with positive GM in broncho-alveolar lavage fluid (BALF), classifying them based on AspICU criteria for suspected IPA (pIPA) or aspiration. Patients with pIPA had higher disease severity than those with aspiration, including higher dialysis rates, organ transplantation, corticosteroid use, and Sequential Organ Failure Assessment (SOFA) score. Aspergillus culture was positive in 47.0% of pIPA cases but only 2.6% of aspiration cases (p < 0.001). SOFA score at first positive GM in BALF independently predicted 28-day mortality. In surgical patients with a positive GM in BALF, aspiration is more likely if there’s no corticosteroid therapy, negative Aspergillus culture, and a history of aspiration events. Diagnosis of pIPA requires Aspergillus culture or prior corticosteroid therapy in this cohort of critically ill patients. [ABSTRACT FROM AUTHOR]

Reduced function or hypomorphic variants in recombination-activating genes (RAG) 1 or 2 result in a broad clinical phenotype including common variable immunodeficiency (CVID) and even adult-onset disease. Milder RAG variants are less characterized. Here we describe the longitudinal course of a milder combined RAG deficiency in 3 of 7 siblings sharing the same RAG2 mutations over a 50-year study. Whole-genome and repertoire sequencing, bacteriophage immunizations, and deep immunophenotyping were used to compare affected and unaffected family members. The clinical phenotype of three affected siblings with hypomorphic RAG deficiency ranged from combined immunodeficiency and early mortality to a late-onset CID with hyper-IgM phenotype. T cells were remarkably similar across affected siblings, yet CDR3 skewing and regulatory T cell defects were not observed. B cell analysis showed elevated unswitched CD27+ and CD21low cells as well as features of an autoreactive antibody repertoire and presence of secreted autoantibodies, yet no clinical autoimmunity was present. Most striking was an expanded polyclonal marginal zone-like B cell population (IgM+IgD+CD27+) utilizing the self-reactive unmutated VH4-34 receptor demonstrating that hypomorphic RAG deficiency can promote expansion of self-reactive B cells. This process, however, was not sufficient to trigger clinical autoimmunity. Utilizing multiple approaches, we functionally measured the specific RAG2 variant effects and assessed how selection and secondary triggers altered the BCR repertoire and immunophenotype overtime. Overall, we demonstrate a broad disease spectrum in siblings with identical hypomorphic RAG deficiency, highlighting that phenotypic divergence can result from expansion of IgM + memory B cells. [ABSTRACT FROM AUTHOR]

The force–length relationship is usually obtained for isometric contractions with maximal activation, but less is known about how sarcomere length affects force during submaximal activation. During submaximal activation, length-dependent alterations in calcium sensitivity, owing to changes in cross-bridge kinetics (rate of attachment and/or detachment), result in an activation-dependent shift in optimal length to longer sarcomere lengths. It is known that sarcomere length, as well as temperature and phosphorylation of the regulatory light chains of myosin, can modify Ca2⁺ sensitivity by altering the probability of cross-bridge interaction. This altered calcium sensitivity is particularly important for submaximal force levels, as it can change the shape of the length dependence of force, with peak force occurring at sarcomere lengths longer than those associated with maximal filament overlap. In athletic contexts, contractions typically do not reach maximal intensity. Therefore, understanding that the ability to produce force under both maximal and submaximal conditions can differ, and that peak force can be generated at different lengths, could influence the development of targeted training regimens optimal for each sport. [ABSTRACT FROM AUTHOR]

Introduction: While ≥ 40 CAG repeat expansions in HTT present a well-established cause of Huntington’s disease (HD), an enrichment of HTT repeat expansions was recently reported also in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including FTD/ALS patients with additional HD neuropathology. This raises the question whether the phenotypic spectrum of HTT expansions can be extended to ALS and FTD, and whether HTT should be considered as a new causative gene of FTD/ALS. If HTT repeat expansions were indeed systematically related to FTD/ALS, one would expect an increased frequency of HTT carriers in FTD/ALS, who can clinically/neuropathologically not be explained better than by the presence of the HTT repeat expansions. Methods: Screening of HTT repeat expansions in 249 consecutive patients with ALS or FTD by short-read genome sequencing took place. The post-mortem neuropathological examination was performed in the identified HTT repeat expansion carrier. Results: One HTT repeat expansion [40/22 repeats (± 1)] was identified in an ALS patient, giving a frequency of 0.4% (1/249) (frequency in the general population: 0.03–0.18%). This patient showed a classic ALS phenotype, but no clinical or imaging signs of HD. Post-mortem brain examination revealed—in addition to ALS-typical degeneration of upper and lower motor neurons with TDP-43 inclusions—HD-typical polyQ-aggregates in gyrus cinguli, striatum and frontal lobe, yet without evidence of striatal degeneration. Conclusions: Our study does not support the notion of an increased frequency of HTT repeat expansions in FTD/ALS. Moreover, the phenotype of the HTT carrier identified can be better explained by two co-existent, but independent diseases: (i) ALS and (ii) presymptomatic HD, which—given the low repeat number—is likely to become manifest only later in life. These findings corroborate the concept that HTT repeat expansions are likely co-existent/coincidental, but not causative in FTD/ALS. [ABSTRACT FROM AUTHOR]

One group of elements attracting more and more attention are so-called technology-critical elements (TCEs). In comparison with legacy pollutants, the anthropogenic impact of TCEs on the environment might still be minor, but various applications introduce them to the most remote places in the world including the marine environment. One area prone to pollution is the Baltic Sea, partly due to the lack of water exchange with the North Sea. In this study, a sediment core from the German Baltic Sea was used to analyze a total of 42 elemental mass fractions. Based on radiometric dating of 210Pb and 137Cs, results were classified in a recent (2020–2000) and a past period (< 1920), calculating background concentrations based on the Median + 2 Median Absolute Deviation (M2MAD) and the Tukey Inner Fence (TIF). Six legacy pollutants (Ni, Cu, Zn, As, Cd, Pb) and six TCEs (Ga, Ge, Nb, La, Gd, Ta) are discussed in detail. Anthropogenic impacts of both groups were assessed, and local enrichment factors were calculated showing an increase for the legacy pollutants (past period (≤ 0.8); recent period (≥ 1.2)), but also a minor increase for Ga, Ge and Nb (past period (0.9); recent period (1.1)). Values ≥ 1.5, indicating anthropogenic impact, were found for Cu, Zn, Cd and Pb, but also for Ge. Proposed background values may be considered as baseline for future studies. [ABSTRACT FROM AUTHOR]

This paper focuses on the critical role of integrative leadership in inter- and transdisciplinary (ITD) research programs. ITD programs have become one of academia's responses to address contemporary sustainability challenges. Fulfilling the promise of such programs is extraordinarily challenging for all involved participants, but especially for program leaders who have to ensure that the perspectives of the involved program participants become truly integrated and that final and useful synthesis outputs are created. We present six core leadership challenges and respective strategies to address them to advance integration within ITD programs. These challenges include (1) mastering complexity and ambiguity, (2) advancing decision-making with lateral leadership, (3) ensuring responsibility and accountability, (4) setting program boundaries, (5) selecting suitable projects, and (6) dealing with misconceptions. We derived these challenges and respective strategies from both leading and studying in-depth three ITD programs focusing on sustainability issues in Switzerland. With this paper, we intend to promote awareness about the range of leadership challenges in ITD programs and provide actionable knowledge, which can support in particular fellow and future leaders, but also funders and heads of research institutions in their efforts to realize the integrative potential of such programs. Image 1: © Eawag: Lisa Deutsch & Sabine Hoffmann; Stückelberger Cartoons: Christof Stückelberger, CC BY-NC-ND 4.0 [ABSTRACT FROM AUTHOR]

When we touch ourselves, the pressure appears weaker compared to when someone else touches us, an effect known as sensory attenuation. Sensory attenuation is spatially tuned and does only occur if the positions of the touching and the touched body-party spatially coincide. Here, we ask about the contribution of visual or proprioceptive signals to determine self-touch. By using a 3D arm model in a virtual reality environment, we dissociated the visual from the proprioceptive arm signal. When a virtual arm was visible indicating self-touch, we found that sensory attenuation generalized across different locations. When no virtual arm was visible, we found sensory attenuation to be strongest when subjects pointed to the position where they felt their arm to be located. We conclude that the spatial tuning of tactile attenuation depends on which signal determines the occurrence of self-touch. When observers can see their hand, the visual signal dominates the proprioceptive determining self-touch in a single visual snapshot. When only the proprioceptive signal is available, the positions of the touching and the touched body-part must be separately estimated and subsequently compared if they overlap in anatomical space. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) therapies effectively treat a broadening spectrum of cancer entities but induce various immune-related side effects (irAEs). Recent reports suggest a correlation between ICI-induced systemic inflammation and thromboembolic events as well as an increased effectiveness by coadministration of anticoagulants. With cancer patients having a higher risk of thrombotic events per se, it is crucial to dissect and characterize the mechanisms that cause pro-coagulative effects induced by systemic tumor therapies and their potential interplay with anti-tumor response. A total of 31 patients with advanced skin cancer treated with either ICIs (n = 24) or BRAF/MEK inhibitors (n = 7) were longitudinally assessed for blood and coagulation parameters before as well as 7, 20 and 40 days after initiation of systemic tumor therapy. Changes were analyzed and compared between both groups. In addition, the influence of coagulation parameters on progression-free, recurrence-free and overall survival was investigated. The ICI cohort presented significantly increased factor VIII activity after one week of therapy (p 0.0225); while, protein S activity was reduced during the whole observation period. Additionally, von Willebrand factor activity and tissue factor concentrations increased under immunotherapy. Similar changes occurred under BRAF/MEK inhibitor therapy (BRAF/MEKi). Increased baseline levels of von Willebrand factor antigen and factor VIII:C before the start of ICI therapy correlated with a significantly higher risk of recurrence for patients receiving adjuvant immunotherapy. The findings suggest the induction of a pro-coagulant state under ICI and BRAF/MEKi and a role of coagulation parameters in the efficacy of ICI therapies. [ABSTRACT FROM AUTHOR]

Sponges harbour complex microbiomes and as ancient metazoans and important ecosystem players are emerging as powerful models to understand the evolution and ecology of symbiotic interactions. Metagenomic studies have previously described the functional features of sponge symbionts, however, little is known about the metabolic interactions and processes that occur under different environmental conditions. To address this issue, we construct here constraint-based, genome-scale metabolic networks for the microbiome of the sponge Stylissa sp. Our models define the importance of sponge-derived nutrients for microbiome stability and discover how different organic inputs can result in net heterotrophy or autotrophy of the symbiont community. The analysis further reveals the key role that a newly discovered bacterial taxon has in cross-feeding activities and how it dynamically adjusts with nutrient inputs. Our study reveals insights into the functioning of a sponge microbiome and provides a framework to further explore and define metabolic interactions in holobionts. Sponges live in symbiosis with diverse microorganisms. This study uses metabolic modelling to show that the microbial symbionts rely on sponge-derived metabolites to maintain community stability and facilitate elemental cycling, and identifies a key microbial clade that drives cross-feeding processes. [ABSTRACT FROM AUTHOR]

The NADPH/NADP+ redox couple is central to metabolism and redox signalling. NADP redox state is differentially regulated by distinct enzymatic machineries at the subcellular compartment level. Nonetheless, a detailed understanding of subcellular NADP redox dynamics is limited by the availability of appropriate tools. Here, we introduce NAPstars, a family of genetically encoded, fluorescent protein-based NADP redox state biosensors. NAPstars offer real-time, specific measurements, across a broad-range of NADP redox states, with subcellular resolution. NAPstar measurements in yeast, plants, and mammalian cell models, reveal a conserved robustness of cytosolic NADP redox homoeostasis. NAPstars uncover cell cycle-linked NADP redox oscillations in yeast and illumination- and hypoxia-dependent NADP redox changes in plant leaves. By applying NAPstars in combination with selective impairment of the glutathione and thioredoxin antioxidative pathways under acute oxidative challenge, we find an unexpected and conserved role for the glutathione system as the primary mediator of antioxidative electron flux. This article presents NAPstars, a family of genetically-encoded biosensors that enable real-time monitoring of NADP redox dynamics across species. The sensors reveal robust NADP redox regulation, cell-cycle-linked NADP oscillations, and glutathione as the major conduit for anti-oxidative electron flux. [ABSTRACT FROM AUTHOR]

The intestinal microbiota plays a critical role in host immunity and might contribute to the significant variation between individuals' vaccine responses. A systematic search was done using MEDLINE and Embase to identify original human studies investigating the association between intestinal microbiota composition and humoral and cellular vaccine responses. In total, 30 publications (26 studies, 14 in infants, 12 in adults), were included. Of these, 26 publications found an association between intestinal microbiota composition and vaccine responses. A beneficial effect of Actynomycetota (particularly Bifidobacterium) and a detrimental effect of Pseudomonadota (particularly Gammaproteobacteria) were observed across studies. Study designs were highly heterogenous, with variation in vaccine type, outcome measure, timing of stool analysis and analysis methods. Overall, studies support the concept that the composition of the intestinal microbiota influences vaccine responses. Further adequately powered studies are needed to confirm this association and inform potential microbiota-targeted interventions to optimise vaccine responses. [ABSTRACT FROM AUTHOR]

Neurological complications in patients undergoing veno-venous extracorporeal membrane oxygenation (V-V ECMO) are challenging, with new intracranial pathologies posing a grave risk. We aimed to evaluate the utility of neuron-specific enolase (NSE) and S100B biomarkers for predicting outcomes in new-onset intracranial pathology during V-V ECMO. A retrospective analysis spanning 2013–2021 at a German university hospital was conducted. Cases with electronically available data on NSE and S100B serum levels, new intracranial pathologies (intracerebral hemorrhage [ICH], subarachnoid hemorrhage [SAH], cerebral ischemia, hypoxic-ischemic encephalopathy [HIE]), and survival during or after V-V ECMO were screened. The primary objective was to assess the prognostic value of NSE and S100B for in-hospital survival during V-V ECMO. Secondary objectives included analyzing clinical characteristics, outcome parameters, and biomarker distribution in V-V ECMO patients. Additionally, the prognostic value of NSE and S100B for in-hospital death and occurrence of intracranial pathology was calculated. Among 744 ECMO recipients, 426 underwent V-V ECMO. No significant differences in disease severity or organ failure scores were observed between groups, except for SAPS at discharge, which was higher in patients with new intracranial pathologies. Patients with new intracranial pathologies had lower median survival and higher in-hospital mortality. Weaning success from ECMO was also significantly reduced in these patients. Cut-off values of 58.4 µg/lfor NSE and 1.52 µg/l for S100B were associated with detrimental outcomes, characterized by significantly reduced median survival. A significant difference in maximum serum NSE concentration was found between patients with and without new intracranial pathology. All screened cases with new intracranial pathology had an unfavorable neurological outcome (modified Rankin Score [mRS] > 3) at discharge, with a higher proportion having an mRS of 6 in the high NSE group. The emergence of intracranial pathology during V-V ECMO significantly increases the risk of death. Changes in NSE and S100B levels serve as valuable follow-up parameters for predicting new intracranial pathology and survival during V-V ECMO therapy. [ABSTRACT FROM AUTHOR]

A new Slovak speech database EWA-DB was created for research purposes aimed at early detection of neurodegenerative diseases from speech. It contains 1649 speakers performing various speech and language tasks, such as sustained vowel phonation, diadochokinesis, naming and picture description. The sample of speakers consists of individuals with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, and healthy controls. In this article we describe the EWA-DB development process, the language and speech task selection, patient and healthy control recruitment, as well as the testing and recording protocol. The structure and content of the database and file formats are described in detail. We assume that the presented database could be suitable for the development of automatic systems predicting the diagnoses of Alzheimer's disease, mild cognitive impairment, and Parkinson's disease from language and speech features. [ABSTRACT FROM AUTHOR]

Over the past few years, several software companies have emerged that offer process mining tools to assist enterprises in gaining insights into their process executions. However, the effective application of process mining technologies depends on analysts who need to be proficient in managing process mining projects and providing process insights and improvement opportunities. To contribute to a better understanding of the difficulties encountered by analysts and to pave the way for the development of enhanced and tailored support for them, this work reveals the challenges they perceive in practice. In particular, we identify 23 challenges based on interviews with 41 analysts, which we validate using a questionnaire survey. We provide insights into the relevancy of the process mining challenges and present mitigation strategies applied in practice to overcome them. While mitigation strategies exist, our findings imply the need for further research to provide support for analysts along all phases of process mining projects on the individual level, but also the technical, group, and organizational levels. [ABSTRACT FROM AUTHOR]

In many Western countries, the ideology of intensive parenting has gained prominence in the discourse of experts, policymakers, and within popular culture. This ideology emphasizes deep parental involvement in emotional, physical, and financial aspects (Lee et al., 2014). Meeting these demanding standards can exert significant pressure on parents, especially on mothers often considered as the primary caregiver. Moreover, these pressures may prompt parents to be highly, and potentially overly, involved in their children's lives. Using data from 146 parent dyads (N = 292 parents; Mage = 47.57 years) of Swiss adolescents, the study explores parental perceptions of pressure to be a perfect parent and its association with one positive (responsiveness) and two negative types of involvement (overprotection and overvaluation). Thereby, we estimated Actor-Partner Interdependence Models (APIM) to examine mutual influences between mothers and fathers. The results indicated that mothers reported experiencing significantly more pressure than fathers. We found evidence for a positive association between perceptions of pressure and parental overprotection among both parents. The results also showed that there was a significant association between feelings of pressure and overvaluation, but only among fathers. Associations between pressure and responsiveness were not significant, and no significant partner effects were observed in any of the models. In conclusion, mothers particularly face heightened pressure to be perfect parents, but both parents may adapt their parenting strategies in response to perceived pressure to be perfect as a parent. These findings highlight the potential issues associated with societal pressures on parents and their impact on parenting behavior. [ABSTRACT FROM AUTHOR]

Poly(ethylene-co-vinyl acetate) is used in numerous industries due to its versatility and increasing development of reinforced foams with a variety of fillers as well as the method of expansion, impacting the properties of foams. By varying the type and content of the incorporated filler as well as the expansion method, it is possible to obtain different cell morphologies even with low filler content in the polymer matrix. On this basis, this study reports the development of EVA foams reinforced with small amounts of micronized graphite and expanded by two expansion methods, namely thermocompression with chemical blowing agents (CBA) and expansion in an autoclave with CO2 in supercritical state as physical blowing agent (PBA). The main results show that the presence of a small amount of graphite reduces the density of foam, significantly increases the size of cells, and consequently, reduces the number of cells per unit area. The CBA foams had a lower density than PBA foams; however, the PBA foams exhibited a more homogeneous morphological structure. [ABSTRACT FROM AUTHOR]

Introduction: The COVID-19 pandemic overwhelmed health systems, resulting in a surge in excess deaths. This study clustered countries based on excess mortality to understand their response to the pandemic and the influence of various factors on excess mortality within each cluster. Materials and Methods: This ecological study is part of the COVID-19 MORtality (C-MOR) Consortium. Mortality data were gathered from 21 countries and were previously used to calculate weekly all-cause excess mortality. Thirty exposure variables were considered in five categories as factors potentially associated with excess mortality: population factors, health care resources, socioeconomic factors, air pollution, and COVID-19 policy. Estimation of Latent Class Linear Mixed Model (LCMM) was used to cluster countries based on response trajectory and Generalized Linear Mixture Model (GLMM) for each cluster was run separately. Results: Using LCMM, two clusters were reached. Among 21 countries, Brazil, the USA, Georgia, and Poland were assigned to a separate cluster, with the mean of excess mortality z-score in 2020 and 2021 around 4.4, compared to 1.5 for all other countries assigned to the second cluster. In both clusters the population incidence of COVID-19 had the greatest positive relationship with excess mortality while interactions between the incidence of COVID-19, fully vaccinated people, and stringency index were negatively associated with excess mortality. Moreover, governmental variables (government revenue and government effectiveness) were the most protective against excess mortality. Conclusion: This study highlighted that clustering countries based on excess mortality can provide insights to gain a broader understanding of countries' responses to the pandemic and their effectiveness. [ABSTRACT FROM AUTHOR]

Abstract Amyloid beta 42 (Abeta42) is the principal trigger of neurodegeneration during Alzheimer’s disease (AD). However, the etiology of its noxious cellular effects remains elusive. In a combinatory genetic and proteomic approach using a yeast model to study aspects of intracellular Abeta42 toxicity, we here identify the HSP40 family member Ydj1, the yeast orthologue of human DnaJA1, as a crucial factor in Abeta42‐mediated cell death. We demonstrate that Ydj1/DnaJA1 physically interacts with Abeta42 (in yeast and mouse), stabilizes Abeta42 oligomers, and mediates their translocation to mitochondria. Consequently, deletion of YDJ1 strongly reduces co‐purification of Abeta42 with mitochondria and prevents Abeta42‐induced mitochondria‐dependent cell death. Consistently, purified DnaJ chaperone delays Abeta42 fibrillization in vitro, and heterologous expression of human DnaJA1 induces formation of Abeta42 oligomers and their deleterious translocation to mitochondria in vivo. Finally, downregulation of the Ydj1 fly homologue, Droj2, improves stress resistance, mitochondrial morphology, and memory performance in a Drosophila melanogaster AD model. These data reveal an unexpected and detrimental role for specific HSP40s in promoting hallmarks of Abeta42 toxicity.

Abstract While some individuals age without pathological memory impairments, others develop age‐associated cognitive diseases. Since changes in cognitive function develop slowly over time in these patients, they are often diagnosed at an advanced stage of molecular pathology, a time point when causative treatments fail. Thus, there is great need for the identification of inexpensive and minimal invasive approaches that could be used for screening with the aim to identify individuals at risk for cognitive decline that can then undergo further diagnostics and eventually stratified therapies. In this study, we use an integrative approach combining the analysis of human data and mechanistic studies in model systems to identify a circulating 3‐microRNA signature that reflects key processes linked to neural homeostasis and inform about cognitive status. We furthermore provide evidence that expression changes in this signature represent multiple mechanisms deregulated in the aging and diseased brain and are a suitable target for RNA therapeutics.

Abstract Adaptive laboratory evolution has proven highly effective for obtaining microorganisms with enhanced capabilities. Yet, this method is inherently restricted to the traits that are positively linked to cell fitness, such as nutrient utilization. Here, we introduce coevolution of obligatory mutualistic communities for improving secretion of fitness‐costly metabolites through natural selection. In this strategy, metabolic cross‐feeding connects secretion of the target metabolite, despite its cost to the secretor, to the survival and proliferation of the entire community. We thus co‐evolved wild‐type lactic acid bacteria and engineered auxotrophic Saccharomyces cerevisiae in a synthetic growth medium leading to bacterial isolates with enhanced secretion of two B‐group vitamins, viz., riboflavin and folate. The increased production was specific to the targeted vitamin, and evident also in milk, a more complex nutrient environment that naturally contains vitamins. Genomic, proteomic and metabolomic analyses of the evolved lactic acid bacteria, in combination with flux balance analysis, showed altered metabolic regulation towards increased supply of the vitamin precursors. Together, our findings demonstrate how microbial metabolism adapts to mutualistic lifestyle through enhanced metabolite exchange.

Ship traffic substantially contributes to air pollution, thus affecting climate and human health. Recently introduced regulations by the International Maritime Organization (IMO) on the fuel sulfur content (FSC) caused a shift in marine fuel onsumption from heavy fuel oils (HFO) to diesel-like distillate fuels, but also to alternative hybrid fuels and the operation of sulfur scrubbers. Using multi-wavelength thermal-optical carbon analysis (MW-TOCA), our study provides emission factors (EF) of carbonaceous aerosol particles and link the fuel composition to features observed in the soot microstructure, which may be exploited in online monitoring by single-particle mass spectrometry (SPMS). Particulate matter from distillate fuels absorbs stronger light of the visible UV and near-infrared range than HFO. However, Simple Forcing Efficiency (SFE) of absorption weighted by EF of total carbon compensated the effect, leading to a net reduction by >50% when changing form HFO to distillate fuels. [ABSTRACT FROM AUTHOR]

The actin-binding protein filamin c (FLNc) is a key mediator in the response of skeletal muscle cells to mechanical stress. In addition to its function as a structural scaffold, FLNc acts as a signaling adaptor which is phosphorylated at S2234 in its mechanosensitive domain 20 (d20) through AKT. Here, we discovered a strong dephosphorylation of FLNc-pS2234 in cultured skeletal myotubes under acute mechanical stress, despite high AKT activity. We found that all three protein phosphatase 1 (PP1) isoforms are part of the FLNc d18-21 interactome. Enzymatic assays demonstrate that PP1 efficiently dephosphorylates FLNc-pS2234 and in vitro and in cells upon PP1 activation using specific modulators. FLNc-pS2234 dephosphorylation promotes the interaction with FILIP1, a mediator for filamin degradation. Altogether, we present a model in which dephosphorylation of FLNc d20 by the dominant action of PP1c prevails over AKT activity to promote the binding of the filamin degradation-inducing factor FILIP1 during acute mechanical stress. [ABSTRACT FROM AUTHOR]

Using classical density functional theory, we study the behavior of dimers, i.e. hard rods of length L = 2 , on a two-dimensional cubic lattice. For deriving a free energy functional, we employ Levy’s prescription which is based on the minimization of a microscopic free energy with respect to the many-body probability under the constraint of a fixed density profile. Using that, we recover the "0D cavity" functional originally found by Lafuente and Cuesta and derive an extension by applying a more general "cluster density functional theory" method introduced by Lafuente and Cuesta as well. Moreover, we introduce a new free energy functional, which is based on approximated configurational probabilities. Both derived free energy functionals are exact on cavities that can hold at most two particles simultaneously. The first functional allows to improve the prediction of the free energy in bulk and both of them improve the prediction in highly confined systems, especially for high packing fractions, in comparison to the "0D cavity" functional. [ABSTRACT FROM AUTHOR]

Background: Quantification of pulmonary edema in patients with acute respiratory distress syndrome (ARDS) by chest computed tomography (CT) scan has not been validated in routine diagnostics due to its complexity and time-consuming nature. Therefore, the single-indicator transpulmonary thermodilution (TPTD) technique to measure extravascular lung water (EVLW) has been used in the clinical setting. Advances in artificial intelligence (AI) have now enabled CT images of inhomogeneous lungs to be segmented automatically by an intensive care physician with no prior radiology training within a relatively short time. Nevertheless, there is a paucity of data validating the quantification of pulmonary edema using automated lung segmentation on CT compared with TPTD. Methods: A retrospective study (January 2016 to December 2021) analyzed patients with ARDS, admitted to the intensive care unit of the Department of Anesthesiology and Critical Care Medicine, University Hospital Mannheim, who underwent a chest CT scan and hemodynamic monitoring using TPTD at the same time. Pulmonary edema was estimated using manually and automated lung segmentation on CT and then compared to the pulmonary edema calculated from EVLW determined using TPTD. Results: 145 comparative measurements of pulmonary edema with TPTD and CT were included in the study. Estimating pulmonary edema using either automated lung segmentation on CT or TPTD showed a low bias overall (− 104 ml) but wide levels of agreement (upper: 936 ml, lower: − 1144 ml). In 13% of the analyzed CT scans, the agreement between the segmentation of the AI algorithm and a dedicated investigator was poor. Manual segmentation and automated segmentation adjusted for contrast agent did not improve the agreement levels. Conclusions: Automated lung segmentation on CT can be considered an unbiased but imprecise measurement of pulmonary edema in mechanically ventilated patients with ARDS. [ABSTRACT FROM AUTHOR]

Purpose: To assess the accuracy of preoperative sonographic staging in patients with primary invasive breast cancer. Methods: We retrospectively analyzed a prospectively kept service database of patients with newly diagnosed, unifocal, cT1-3, invasive breast cancer. All patients were diagnosed at a single center institution between January 2013 and December 2021. Clinical T stage was assessed preoperatively by ultrasound and correlated with the definite postoperative pathologic T stage. Demographics, clinical and pathological characteristics were collected. Factors influencing accuracy, over- and underdiagnosis of sonographic staging were analyzed with multivariable regression analysis. Results: A total of 2478 patients were included in the analysis. Median patients' age was 65 years. 1577 patients (63.6%) had clinical T1 stage, 864 (34.9%) T2 and 37 (1.5%) T3 stage. The overall accuracy of sonography and histology was 76.5% (n = 1896), overestimation was observed in 9.1% (n = 225) of all cases, while underestimation occurred in 14.4% (n = 357) of all cases. Accuracy increased when clinical tumor stage cT was higher (OR 1.23; 95% CI 1.10–1.38, p ≤ 0.001). The highest accuracy was seen for patients with T2 stage (82.8%). The accuracy was lower in Luminal B tumors compared to Luminal A tumors (OR 0.71; 95% CI 0.59–0.87, p ≤ 0.001). We could not find any association between sonographic accuracy in HER2 positive patients, and demographic characteristics, or tumor-related factors. Conclusion: Our unicentric study showed a high accuracy of sonography in predicting T stage, especially for tumors with clinical T2 stage. Tumor stage and biological tumor factors do affect the accuracy of sonographic staging. [ABSTRACT FROM AUTHOR]

Over the past few decades, the topic of recycling has become increasingly prominent in the field of sustainable materials and circular economy. One significant challenge is the physical separation of different types of plastics to obtain recyclates of one plastic type as pure as possible with comparable quality and properties to those of virgin material. Given the substantial effort involved in such separation, small amounts of contamination from other plastics may be tolerated. However, these contaminations must be monitored to ensure high-level recyclate quality. In recent years, compact, low-cost ion mobility spectrometers (IMS) with high analytical performance have been developed, and have thus become widely used in a variety of sensing applications. Due to their high sensitivity, IMS are particularly suited for detecting lowest concentration levels of various compounds, as required for the detection of impurities in recyclate quality monitoring. When coupled to a miniature gas chromatograph (GC), GC-IMS reach even higher separation power while being still compact. To bring recyclate samples to the gas phase, pyrolysis (Py) is used in this work. A first feasibility study was conducted to assess the potential of such a pyrolysis–gas chromatography-ion mobility spectrometer (Py-GC-IMS) with the objective of detecting contaminations of polyethylene terephthalate (PET) in polyethylene (PE) recyclates. The study clearly demonstrates the ability to identify PET-related fingerprints while suppressing the PE background matrix by design so that Py-GC-IMS seems a promising approach for in-process monitoring PET contaminations in PE recyclates. [ABSTRACT FROM AUTHOR]

Purpose: To study survival outcomes and prognostic factors in patients undergoing whole brain radiation therapy (WBRT) for brain metastases in the contemporary setting. Methods: Patients undergoing WBRT from 2013–2021 were retrospectively included in an ethics-approved institutional database. Patient and treatment characteristics were assessed, including patient age, primary tumor histology, Karnofsky Performance Status (KPS), extracranial disease, as well as WBRT dose. Overall survival (OS) was calculated from onset of WBRT using the Kaplan-Meier method. Results: A total of 328 patients (median age 63 years) were included. Most patients (52%) had ≥ 10 brain metastases, and 17% had leptomeningeal disease. WBRT was delivered with 10 × 3 Gy (64%), 5 × 4 Gy (25%), or other regimens (11%). Median follow-up was 4.4 months (range, 0.1–154.3), and median OS was 4.7 months (95%CI, 3.8–6.0). OS differed between histologies (p = 0.01), with the longest survival seen in breast cancer (median 7.7 months). Patients with KPS of 90–100 survived for a median of 8.3 months, compared to 4.1 months with KPS 70–80, and 1.7 months with KPS < 70 (p < 0.01). Multivariate analyses revealed that KPS had the largest impact on survival. Patients who received a WBRT dose of ≥ 30 Gy also had a reduced risk of death (HR 0.45; p < 0.001). Survival differed between subgroups reclassified according to the Rades scoring system (p < 0.01). Conclusion: Survival outcomes of patients undergoing WBRT in the contemporary era appear comparable to historical cohorts, although individual patient factors need to be considered. Patients with otherwise favorable prognostic factors may benefit from longer-course WBRT. [ABSTRACT FROM AUTHOR]

Radiation-induced morphea (RIM) is a rare complication of radiotherapy presenting as inflammatory fibrosis, most commonly reported in breast cancer patients. As underlying disease mechanisms are not well understood, targeted therapies are lacking. Since fibroblasts are the key mediators of all fibroproliferative diseases, this study aimed to characterize patient-derived fibroblasts to identify therapeutic targets. We studied primary human control and RIM-fibroblasts on a functional and molecular basis, analyzed peripheral blood and tissue samples and conducted, based on our findings, a treatment attempt in one patient. In RIM, we identified a distinct myofibroblast phenotype reflected by increased alpha-smooth-muscle-actin (αSMA) expression, reduced proliferation and migration rates, and overexpression of osteopontin (OPN). Our RNA sequencing identified aberrant Myc activation as a potential disease driver in RIM fibroblasts, similar to previous findings in systemic sclerosis. Treatment with the anti-inflammatory drug mesalazine reversed the myofibroblast phenotype by targeting Myc. Based on these findings, a patient with RIM was successfully treated with mesalazine, resulting in reduced inflammation and pain and tissue softening, while serum OPN was halved. The present study provides a comprehensive characterization of RIM fibroblasts, suggests a disease-driving role for Myc, demonstrates promising antifibrotic effects of mesalazine and proposes OPN as a biomarker for RIM. [ABSTRACT FROM AUTHOR]