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Background Diastolic dysfunction with delayed relaxation and abnormal passive elastic properties has been described in patients with severe pressure overload hypertrophy. The purpose of this study was to evaluate the time course of rotational motion of the left ventricle in patients with aortic valve stenosis using myocardial tagging.Methods Myocardial tagging is a non-invasive method based on magnetic resonance which makes it possible to label (‘tag’) specific myocardial regions. From the motion of the tag’s cardiac rotation, radial displacement and translational motion can be determined. In 12 controls and 13 patients with severe aortic valve stenosis systolic and diastolic wall motion was assessed in an apical and basal short axis plane.Results The normal left ventricle performs a systolic wringing motion around the ventricular long axis with clockwise rotation at the base (−4·4±1·6°) and counterclockwise rotation at the apex (+6·8±2·5°) when viewed from the apex. During early diastole an untwisting motion can be observed which precedes diastolic filling. In patients with aortic valve stenosis systolic rotation is reduced at the base (−2·4±2·0°;P<0·01) but increased at the apex (+12·0±6·0°;P<0·05). Diastolic untwisting is delayed and prolonged with a decrease in normalized rotation velocity (−6·9±1·1s−1) when compared to controls (−10·7±2·2s−1;P<0·001). Maximal systolic torsion is 8·0±2·1° in controls and 14·1±6·4° (P<0·01) in patients with aortic valve stenosis.Conclusions Left ventricular pressure overload hypertrophy is associated with a reduction in basal and an increase in apical rotation resulting in increased torsion of the ventricle. Diastolic untwisting is delayed and prolonged. This may explain the occurrence of diastolic dysfunction in patients with severe pressure overload hypertrophy. [ABSTRACT FROM PUBLISHER]

Several salts of cubane-1,4-dimethylnitrocarbamate (CMNC) were synthesized. The divalent CMNC is deprotonated by alkaline, alkaline earth metal, and nonmetal bases to form the corresponding salts. The compounds were characterized and analyzed by multinuclear NMR and IR spectroscopy, mass spectrometry, elemental analysis, single crystal X-ray, and thermoanalytical techniques. The energies of formation for the salts were calculated using Gaussian. Detonation performances were calculated with the Explo5 (V6.03) computer code. The sensitivities toward impact and friction were determined and compared to the neutral CMNC.

Purpose: This study aimed to assess the feasibility of a comprehensive psychosocial intervention for families coping with parental cancer., Methods: A quasi-experimental trial with intervention and control group, employing a mixed-methods approach, was conducted. A total of 472 families affected by parental cancer participated. The feasibility of the intervention was evaluated based on study monitoring measures (on-site visits, team supervision meeting observations, case conference observations, best practice workshops, coordinating information exchange between intervention sites, and reviewing intervention documentation), process evaluation (semi-structured interviews, focus group discussion) and survey data. Data analysis involved thematic coding and descriptive statistics., Results: The intervention was well-received by the participating families, with a high degree of acceptance observed. The feasibility of the intervention was found to be associated with specific dynamics within each family system and the motivation of the family members. The success of the intervention was described as dependent on the family-centered arrangement of the encounters, including factors such as frequency, duration, and mode, which greatly influenced its overall acceptability., Conclusion: The family-scout intervention demonstrates its feasibility as an effective intervention to reduce the burden experienced by families coping with parental cancer. Psychosocial oncology services should continue to develop and implement family-centered interventions to offer support to families during their cancer journey., Trial Registration: ClinicalTrials.gov, NCT04186923. Retrospectively registered on 4 December 2019., (© 2024. The Author(s).)

Cytokines induce functional and metabolic adaptations in immune cells, typically through transcriptional responses that can be influenced by other extracellular signals and by intracellular factors. The binding of the cytokine interleukin-4 (IL-4) to its receptor induces the phosphorylation and activation of the transcription factor STAT6. The aryl hydrocarbon receptor (AhR), a transcription factor activated by various endogenous and microbe-derived metabolites, modulates the responses of immune cells to danger signals or inflammatory mediators such as cytokines. Here, we investigated cross-talk between the AhR and signaling stimulated by IL-4 in human and mouse monocytes. AhR activation was required for a subset of IL-4-induced transcriptional responses and inhibited the IL-4-induced metabolic switch to fatty acid β-oxidation. The promoters of the genes that were induced by IL-4 in an AhR-dependent manner lacked canonical AhR binding sites, implying a nongenomic mechanism of AhR action. Mechanistically, AhR activation reduced the activity of SHP-1, a phosphatase that targets and inhibits STAT6, and prolonged STAT6 phosphorylation and binding to specific target loci, thus extending the duration of STAT6 activity. Our results identify AhR as a key player in the molecular control of responses to IL-4 in monocytes and suggest a nongenomic mechanism through which AhR ligands may influence the functional responses of cells to IL-4.

Many photocatalysts were initially developed or used as emitters for organic light emitting diodes (OLEDs). This feature article summarizes the different generations of OLED emitters and connects the photophysical processes with those relevant for photocatalysis. The focus is on the general properties OLED emitters and photocatalysts are designed for and how photocatalysis has benefitted from OLED research. Sometimes optimization of an OLED emitter leads to a better photocatalyst while some properties are optimized into opposite directions. To discover new classes of photocatalysts in the future it is important to consider what good OLED emitters and good photocatalyst have in common and where they diverge. Within recent years, fully organic thermally activated delayed fluorescence (TADF) emitters had the most significant impact in both fields and thus are discussed with specific focus.

Objective: Radiographic assessment of sacroiliac joints (SIJs) according to the modified New York (mNY) criteria is key in the classification of axial spondyloarthritis but has moderate interreader agreement. We aimed to investigate the improvements of the reliability in scoring SIJ radiographs after applying an online real-time iterative calibration (RETIC) module, in addition to a slideshow and video alone., Methods: Nineteen readers, randomized to 2 groups (A or B), completed 3 calibration steps: (1) review of manuscripts, (2) review of slideshow and video with group A completing RETIC, and (3) re-review of slideshow and video with group B completing RETIC. The RETIC module gave instant feedback on readers' gradings and continued until predefined reliability (κ) targets for mNY positivity/negativity were met. Each step was followed by scoring different batches of 25 radiographs (exercises I to III). Agreement (κ) with an expert radiologist was assessed for mNY positivity/negativity and individual lesions. Improvements by training strategies were tested by linear mixed models., Results: In exercises I, II, and III, mNY κ were 0.61, 0.76, and 0.84, respectively, in group A; and 0.70, 0.68, and 0.86, respectively, in group B (ie, increasing, mainly after RETIC completion). Improvements were observed for grading both mNY positivity/negativity and individual pathologies, both in experienced and, particularly, inexperienced readers. Completion of the RETIC module in addition to the slideshow and video caused a significant κ increase of 0.17 (95% CI 0.07-0.27; P = 0.002) for mNY-positive and mNY-negative grading, whereas completion of the slideshow and video alone did not (κ = 0.00, 95% CI -0.10 to 0.10; P = 0.99)., Conclusion: Agreement on scoring radiographs according to the mNY criteria significantly improved when adding an online RETIC module, but not by slideshow and video alone.

Bioinspired from cationic antimicrobial peptides, sequence-defined triazolium-grafted peptoid oligomers (6- to 12-mer) were designed to adopt an amphipathic helical polyproline I-type structure. Their evaluation on a panel of bacterial strains ( Escherichia coli , Pseudomonas aeruginosa , Staphylococcus aureus , and Enterococcus faecalis ), pathogenic fungi ( Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus ), and human cells (hRBC, BEAS-2B, Caco-2, HaCaT, and HepG2) enabled the identification of two heptamers with improved activity to selectively fight Staphylococcus aureus pathogens. Modulation of parameters such as the nature of the triazolium and hydrophobic/lipophilic side chains, the charge content, and the sequence length drastically potentiates activity and selectivity. Besides, the ability to block the proinflammatory effect induced by lipopolysaccharide or lipoteichoic acid was also explored. Finally, biophysical studies by circular dichroism and fluorescence spectroscopies strongly supported that the bactericidal effect of these triazolium-grafted oligomers was primarily due to the selective disruption of the bacterial membrane.

Background: In kidney transplant recipients (KTR), BK polyomavirus-associated nephropathy (BKPyVAN) is a major cause of graft loss. To facilitate the clearance of BKPyV-DNAemia, reduction of immunosuppression is currently the treatment of choice but may increase the risk of graft rejection., Methods: This international CERTAIN study was designed to determine the risk of alloimmune response and graft dysfunction associated with immunosuppression reduction for BKPyV treatment in 195 pediatric KTR., Results: BKPyV-DNAemia was associated with a more than twofold increased risk of late T cell-mediated rejection (TCMR) (HR 2.22, p = 0.024), of de novo donor-specific HLA antibodies (dnDSA) and/or antibody-mediated rejection (ABMR) (HR 2.64, p = 0.002), and of graft function deterioration (HR 2.73, p = 0.001). Additional independent risk factors for dnDSA/ABMR development were a higher HLA mismatch (HR 2.72, p = 0.006) and re-transplantation (HR 6.40, p = 0.000). Other independent predictors of graft function deterioration were TCMR (HR 3.98, p = 0.003), higher donor age (HR 1.03, p = 0.020), and re-transplantation (HR 3.56, p = 0.013)., Conclusions: These data indicate that reduction of immunosuppression for BKPyV-DNAemia management is associated with increased alloimmune response in pediatric KTR. Therefore, regular dnDSA screening and close monitoring of graft function in case of BKPyV-DNAemia followed by subsequent reduction of immunosuppressive therapy are recommended., (© 2024. The Author(s).)

Despite advances in treatment modalities, bone tumour therapies still face significant challenges. Severe side effects of conventional approaches, such as chemo- and radiation therapy, result in poor survival rates and high tumour recurrence rates, which are the most common issues that need to be improved upon. The aim of this study was to evaluate the therapeutic properties of 45S5 bioactive glass (BG) for targeting bone tumours. The viability of the cells derived from osteosarcoma, chondrosarcoma, and giant cell tumours was significantly reduced in the presence of 45S5-BG. In contrast, the viability of non-malignant osteoblast-like cells, chondrocytes, and bone marrow-derived stromal cells was not or only slightly affected. While alterations to the particle surface induced by heat treatment, acid etching, or incubation in a simulated body fluid had only minor effects on cytotoxicity, reducing the particle size or sintering the material significantly improved the cytotoxic effect of 45S5-BG. Further, using a chicken chorioallantoic membrane assay, the co-transplantation of 45S5-BG resulted in a significant reduction in tumour formation in vivo. Given the known positive effects of BGs on bone regeneration, our findings suggest that 45S5-BG holds great potential for the development of new and effective bone tumour therapies, with minimal side effects on non-malignant cells and simultaneous contribution to bone healing.

Gamma aminobutyric acid type A receptors (GABA A Rs) play a key role in the mammalian central nervous system (CNS) as drivers of neuroinhibitory circuits, which are commonly targeted for therapeutic purposes with potentiator drugs. However, due to their widespread expression and strong inhibitory action, systemic pharmaceutical potentiation of GABA A Rs inevitably causes adverse effects regardless of the drug selectivity. Therefore, therapeutic guidelines must often limit or exclude clinically available GABA A R potentiators, despite their high efficacy, good biodistribution, and favorable molecular properties. One solution to this problem is to use drugs with light-dependent activity (photopharmacology) in combination with on-demand, localized illumination. However, a suitable light-activated potentiator of GABA A Rs has been elusive so far for use in wildtype mammals. We have met this need by developing azocarnil, a diffusible GABAergic agonist-potentiator based on the anxiolytic drug abecarnil that is inactive in the dark and activated by visible violet light. Azocarnil can be rapidly deactivated with green light and by thermal relaxation in the dark. We demonstrate that it selectively inhibits neuronal currents in hippocampal neurons in vitro and in the dorsal horns of the spinal cord of mice, decreasing the mechanical sensitivity as a function of illumination without displaying systemic adverse effects. Azocarnil expands the in vivo photopharmacological toolkit with a novel chemical scaffold and achieves a milestone toward future phototherapeutic applications to safely treat muscle spasms, pain, anxiety, sleep disorders, and epilepsy.

Optical pooled screening (OPS) is a scalable method for linking image-based phenotypes with cellular perturbations. However, it has thus far been restricted to relatively low-plex phenotypic readouts in cancer cell lines in culture due to limitations associated with in situ sequencing of perturbation barcodes. Here, we develop PerturbView, an OPS technology that leverages in vitro transcription to amplify barcodes before in situ sequencing, enabling screens with highly multiplexed phenotypic readouts across diverse systems, including primary cells and tissues. We demonstrate PerturbView in induced pluripotent stem cell-derived neurons, primary immune cells and tumor tissue sections from animal models. In a screen of immune signaling pathways in primary bone marrow-derived macrophages, PerturbView uncovered both known and novel regulators of NF-κB signaling. Furthermore, we combine PerturbView with spatial transcriptomics in tissue sections from a mouse xenograft model, paving the way to in situ screens with rich optical and transcriptomic phenotypes. PerturbView broadens the scope of OPS to a wide range of models and applications., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Polymeric carbon nitride has attracted significant interest in heterogeneous photocatalysis due to its activity under visible-light irradiation. Herein, we report on using carbon nitride-coated NMR tubes for in-situ studies of photocatalytic reaction mechanisms. In a first step, we exploited carbon nitride-coated crimp vials as batch photoreactors for visible photocatalytic fluorinations of unactivated C(sp3)-H bonds, with moderate to excellent yields and reusability over multiple cycles. Eventually, carbon nitride-coated NMR tubes were used as a photoreactor by coupling them with optical fiber irradiation directly inside the spectrometer. This enabled us to follow the reaction with in-situ NMR spectroscopy identifying reactive intermediates otherwise elusive in conventional analyses. The method provides advantages for the study of photocatalytic mechanisms of complex reactions and substantially reduces the need of comparative tests for depicting reaction intermediates and conversion pathways., (© 2024 Wiley‐VCH GmbH.)

Biocrusts are crucial components of Arctic ecosystems, playing significant roles in carbon and nitrogen cycling, especially in regions where plant growth is limited. However, the microbial communities within Arctic biocrusts and their strategies for surviving the harsh conditions remain poorly understood. In this study, the microbial profiles of Arctic biocrusts across different seasons (summer, autumn, and winter) were investigated in order to elucidate their survival strategies in extreme conditions. Metagenomic and metatranscriptomic analyses revealed significant differences in microbial community composition among the sites located in different elevations. The bacterial communities were dominated by Actinobacteria and Proteobacteria, while the fungal communities were mainly represented by Ascomycota and Basidiomycota, with lichenized and saprotrophic traits prevailing. Cyanobacteria were primarily composed of heterocystous cyanobacteria. Furthermore, the study identified molecular mechanisms underlying cold adaptation, including the expression of heat shock proteins and cold-inducible RNA helicases in cyanobacteria and fungi. Overall, the microbial communities appear to be permanently well adapted to the extreme 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 Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Digital mental health interventions (DMHIs) are capable of closing gaps in the prevention and therapy of common mental disorders. Despite their proven effectiveness and approval for prescription, use rates remain low. The reasons include a lack of familiarity and knowledge as well as lasting concerns. Medical students were shown to have a comparatively higher risk for common mental disorders and are thus an important target group for raising awareness about DMHIs. At best, knowledge is already imparted during medical school using context-sensitive information strategies. Yet, little is known about medical students' information preferences regarding DMHIs., Objective: This study aims to explore information preferences for DMHIs for personal use among medical students in Germany., Methods: A discrete choice experiment was conducted, which was developed using an exploratory sequential mixed methods research approach. In total, 5 attributes (ie, source, delivery mode, timing, recommendation, and quality criteria), each with 3 to 4 levels, were identified using formative research. Data were analyzed using logistic regression models to estimate preference weights and the relative importance of attributes. To identify subgroups of students varying in information preferences, we additionally performed a latent class analysis., Results: Of 309 participants, 231 (74.8%) with reliable data were included in the main analysis (women: 217/309, 70.2%; age: mean 24.1, SD 4.0 y). Overall, the conditional logit model revealed that medical students preferred to receive information about DMHIs from the student council and favored being informed via social media early (ie, during their preclinic phase or their freshman week). Recommendations from other students or health professionals were preferred over recommendations from other users or no recommendations at all. Information about the scientific evidence base was the preferred quality criterion. Overall, the timing of information was the most relevant attribute (32.6%). Latent class analysis revealed 2 distinct subgroups. Class 1 preferred to receive extensive information about DMHIs in a seminar, while class 2 wanted to be informed digitally (via email or social media) and as early as possible in their studies., Conclusions: Medical students reported specific needs and preferences regarding DMHI information provided in medical school. Overall, the timing of information (early in medical education) was considered more important than the information source or delivery mode, which should be prioritized by decision makers (eg, members of faculties of medicine, universities, and ministries of education). Study findings suggest general and subgroup-specific information strategies, which could be implemented in a stepped approach. Easily accessible digital information may promote students' interest in DMHIs in the first step that might lead to further information-seeking behavior and the attendance of seminars about DMHIs in the second step., (©Markus Vomhof, Jessica Tabea Bau, Pia Hüter, Stefan Stehl, Burkhard Haastert, Adrian Loerbroks, Andrea Icks, Stella Teresa Calo, Luca Schuster, Claudia R Pischke, Nadja Kairies-Schwarz, Peter Angerer, Jennifer Apolinário-Hagen. Originally published in JMIR Formative Research (https://formative.jmir.org), 04.10.2024.)

A mild and concise diazoarylation of [1.1.1]propellane is described, which provides a modular approach to arylated diazo bicyclopentanes (BCPs). This reaction proceeds smoothly under basic conditions without requiring other additives or catalysts. The substrate scope shows that various electron-withdrawing and electron-donating groups are tolerated, and the subsequent modifications provide a novel avenue for assembling arylamino-BCP analogs.

In spring 2022, an increase in metallo-β-lactamase-producing Pseudomonas aeruginosa (MBL-Pa) infections was detected in a hospital in Upper Austria. To identify the source of infection and to stop further transmissions, an epidemiological outbreak investigation including whole-genome sequencing (WGS)-based typing was conducted. The final case definition included cases admitted to the hospital between 2020 and 2023 with an MBL-Pa in one of the three genomic clusters identified. In addition, the investigation was extended to include historical cases from 2017. Core genome multilocus sequence typing was performed to assess the genetic relatedness between the isolates. Fifty-four clinical P. aeruginosa isolates and eight P. aeruginosa isolates from the hospital environment were obtained. All but nine isolates grouped into one of three genomic clusters (ST235/ bla VIM-1 , ST111/ bla VIM-2 , or ST621/ bla IMP-13 ), which were considered to be distinct, prolonged outbreaks involving 47 out of 52 cases. The most likely source of infection for cluster 1 (ST111/ bla VIM-2 ) and cluster 2 (ST235/ bla VIM-1 ) was sinks in the intensive care unit (ICU) washroom. Cluster 3 clone (ST621/ bla IMP-13 ) could have originated in the urology ward in 2020 and then spread to the ICU years later. However, the nosocomial origin of this clone could not be proven. In March 2023, following the implementation of control measures (gowning, patient isolation, screening, and daily disinfection), no further MLB-Pa was detected, and the outbreaks were considered to be over. As ICUs play an important role in the transmission of P. aeruginosa , emphasis should be placed on genomic surveillance, infection prevention, and control in such wards., Importance: The significance of our work lies in the successful resolution of three prolonged outbreaks of MBL-Pa infections in a hospital in Upper Austria. Through a comprehensive epidemiological investigation coupled with WGS-based typing of P. aeruginosa isolates, the study identified three distinct genomic clusters responsible for prolonged outbreaks involving 47 cases. The investigation pinpointed sinks in the ICU washroom as the likely source of infection for two of the clusters. The study demonstrates the effectiveness of control measures such as hand hygiene, gowning, patient isolation, screening, and disinfection in stopping further transmission and bringing the outbreaks to a close. This underscores the critical role of genomic surveillance and control measures, particularly in high-risk settings like ICUs, in reducing nosocomial transmission of MBL-Pa infections., Competing Interests: The authors declare no conflict of interest.

A healthy mammalian central nervous system (CNS) harbors a diverse population of leukocytes including members of the mononuclear phagocyte system (MPS). Exerting their specific functions, CNS tissue-resident macrophages as well as associated monocytes and dendritic cells (DCs) maintain CNS homeostasis. Under neuroinflammatory conditions, leukocytes from the systemic immune compartment invade the CNS. This review focuses on the newly discovered roles of the MPS in autoimmune neuroinflammation elicited by encephalitogenic T cells. We propose that CNS-associated DCs act as gatekeepers and antigen-presenting cells that guide the adaptive immune response while bone marrow (BM)-derived monocytes contribute to immunopathology and tissue damage. By contrast, CNS-resident macrophages primarily support tissue function and promote the repair and maintenance of CNS functions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The phylogenetic relationships of the small-bodied catarrhine Pliobates cataloniae (∼11.6 Ma, NE Iberian Peninsula) have been controversial since its original description. However, the recent report of additional dentognathic remains has supported its crouzeliid pliopithecoid status. Based on the available hypodigm, the molar enamel-dentine junction (EDJ) shape of P. cataloniae is compared with that of other pliopithecoids from the same basin as well as both extinct and extant hominoids to further evaluate its pliopithecoid affinities. We also quantitatively compare the EDJ shape among these taxa by means of landmark-based three-dimensional geometric morphometrics using principal component analysis (PCA), canonical variate analysis, and between-group PCA. Permutation tests are performed to test whether Pliobates variation exceeds that of extant hominoid genera. Results indicate that Pliobates is similar in molar EDJ shape to other pliopithecoids, particularly crouzeliids. The variation displayed by Pliobates upper molars is less marked at the EDJ level than at the outer enamel surface, probably owing to differential enamel wear and intraspecific differences in enamel thickness. Multivariate analyses of EDJ shape show that all pliopithecoids (including Pliobates) cluster together in the PCAs, canonical variate analyses, and between-group PCAs and occupy a different portion of the morphospaces from extinct and extant hominoids. Posterior and typicality probabilities strongly support the classification of Pliobates as a pliopithecoid, wheras permutation tests fail to reject the single-genus hypothesis for the P. cataloniae hypodigm. We conclude that P. cataloniae is a crouzeliid pliopithecoid, as recently supported by cladistic analyses of craniodental characters, and that previous cladistic results that supported a stem hominoid status are attributable to postcranial convergences with crown hominoids. Our results further highlight the potential of three-dimensional geometric morphometrics analyses of the EDJ shape for better informing fossil primate alpha-taxonomy by means of quantitatively testing hypotheses about tooth shape variation., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tertiary lymphoid structures (TLS) resemble follicles of secondary lymphoid organs and develop in nonlymphoid tissues during inflammation and cancer. Which cell types and signals drive the development of TLS is largely unknown. To investigate early events of TLS development in the lungs, we repeatedly instilled p(I:C) plus ovalbumin (Ova) intranasally. This induced TLS ranging from lymphocytic aggregates to organized and functional structures containing germinal centers. We found that TLS development is independent of FAP + fibroblasts, alveolar macrophages, or CCL19 but crucially depends on type I interferon (IFN-I). Mechanistically, IFN-I initiates two synergistic pathways that culminate in the development of TLS. On the one hand, IFN-I induces lymphotoxin (LT)α in lymphoid cells, which stimulate stromal cells to produce the B-cell-attracting chemokine CXCL13 through LTβR-signaling. On the other hand, IFN-I is sensed by stromal cells that produce the T-cell-attracting chemokines CXCL9, CXCL10 as well as CCL19 and CCL21 independently of LTβR. Consequently, B-cell aggregates develop within a week, whereas follicular dendritic cells and germinal centers appear after 3 weeks. Thus, sustained production of IFN-I together with an antigen is essential for the induction of functional TLS in the lungs., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Skin cancer risk is increased by exposure to ultraviolet radiation (UVR). Because UVR exposure accumulates over time and lighter skin is more susceptible to UVR, age and skin tone are risk factors for skin cancer. However, measurements of somatic mutations in healthy-appearing skin have not been used to calculate skin cancer risk. In this study, we developed a noninvasive test that quantifies somatic mutations in healthy-appearing sun-exposed skin and applied it to a 1038-subject cohort. Somatic mutations were combined with other known skin cancer risk factors to train a model to calculate risk. The final model (DNA-Skin Cancer Assessment of Risk) was trained to predict personal history of skin cancer from age, family history, skin tone, and mutation count. The addition of mutation count significantly improved model performance (OR = 1.3, 95% confidence interval = 1.14-1.48; P = 5.3 × 10 -6 ) and made a more significant contribution than skin tone. Calculations of skin cancer risk matched the known United States population prevalence, indicating that DNA-Skin Cancer Assessment of Risk was well-calibrated. In conclusion, somatic mutations in healthy-appearing sun-exposed skin increase skin cancer risk, and mutations capture risk information that is not accounted for by other risk factors. Clinical utility is supported by the noninvasive nature of skin sample collection through adhesive patches., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Biomechanical stress may exacerbate inflammation in psoriatic arthritis (PsA). This study aimed to investigate disease activity, work disability, and drug response/retention rates in PsA patients among two different occupation's types: blue-collar workers (BCol) with manual labor versus white-collar workers (WCol) with sedentary occupations. PsA patients registered in the Swiss cohort (SCQM) were classified as BCol or WCol workers and assessed at the initiation of a biologic or targeted synthetic disease-modifying anti-rheumatic drug (b-/tsDMARD). We compared the baseline characteristics at treatment start and the DAS28-CRP for the 1-year remission. Treatment retention was investigated using Kaplan-Meier curves and Cox regression analysis. Multivariable models were adjusted for potential confounders. Of 564 patients, 29% were BCol, and 71% were WCol workers. Baseline disease activity was comparable between both groups. BCol workers were predominantly male (79.8%) and more work disabled at baseline (84.0% vs. 27.9%; p < 0.01). One hundred seventy-four treatment courses (TCs) of 165 PsA patients were included for longitudinal analysis. Occupation did not significantly influence the achievement of DAS28-CRP remission at 1 year. Kaplan-Meier analysis (n = 671) indicated longer retention for BCol workers (mean retention duration: 3.15 years vs. 2.15 years, (p = 0.006). However, adjusted Cox regression analysis did not corroborate these findings. This study indicates that physically demanding occupations correlate with increased rates of work disability among PsA patients, while treatment response seems to be unaffected by the patients' occupation type. Additional research is required to thoroughly comprehend the relationship between physical workload, disease activity, and treatment outcomes. Key Points • This study indicates that physically demanding occupations correlate with increased rates of work disability among PsA patients. • The treatment response among of PsA patients seems unaffected by the patients' occupation type., (© 2024. The Author(s).)

Purpose: Soft tissue tumors (STT) are difficult to diagnose accurately, and distinguishing between benign and malignant tumors is challenging. Lipoma is the most common STT, while atypical lipomatous tumors (ALT) can dedifferentiate into malignant lipomatous tumors like grade 1 liposarcoma and require more radical therapy. This study aims to investigate the potential of contrast-enhanced ultrasound (CEUS) to differentiate between lipoma and ALT based on tumor perfusion., Materials and Methods: We prospectively examined 52 patients who were scheduled for biopsy for suspected lipoma or ALT. The CEUS examination was performed using SonoVue as a contrast agent to quantify tumor perfusion using VueBox V7.1 software. Peak enhancement (PE), rise time (RT), wash-in perfusion index (WiPI), and wash-out rate (WoR) were used to assess contrast enhancement inside the STT., Results: Among 50 tumors examined, 30 were lipomas, and 20 were ALTs. We found significant differences in perfusion between lipomas and ALTs (PE: 49.22 ± 45.75 a.u. vs. 165.67 ± 174.80; RT: 23.86 ± 20.47s vs. 10.72 ± 5.34 s; WiPI: 33.06 ± 29.94 dB vs. 107.21 ± 112.43 dB; WoR: 2.44 ± 3.70 dB/s vs. 12.75 ± 15.80 dB/s; p<.001). ROC analysis of PE resulted in a diagnostic accuracy of 74% for the detection of an ALT, and 77% for the detection of a lipoma., Conclusion: CEUS may enhance the differential diagnosis of benign lipomas and ALTs, with ALTs showing higher levels of perfusion. If larger prospective studies confirm these findings, CEUS could enhance diagnostic accuracy, guide surgical planning, and potentially reduce unnecessary treatments for patients presenting with ambiguous lipomatous tumors like lipoma or ALT., Competing Interests: Prof. Tobias Renkawitz has received research support and personal fees from Arbeitsgemeinschaft Endoprothetik (AE), DGOU, DGOOC; BVOU, DePuy International, Otto Bock Foundation, Deutsche Arthrose Hilfe, Aesculap, Zimmer, Stiftung Oskar Helene Heim Berlin, VielberthFoundation Regensburg, the German Ministry of Education and Research as well as the German Federal Ministry of Economic Cooperation and Development. He is Medical Director and Chair at the Orthopaedic Department at Heidelberg University Hospital, board member of the German Society for Orthopaedics and Trauma (DGOOC), vice president of the Professional Association of Orthopaedic Specialists and Trauma Surgeons (BVOU) and President of the German Academy of Orthopedic and Trauma Surgeons (AOUC). He is on the editorial board of „Die Orthopädie“, „Die Unfallchirurgie“, „OUMN“ (Springer, Heidelberg, Berlin, New York) and on the international advisory board of the Journal of the American Academy of Orthopedic Surgeons (AAOS) (Wolters Kluwer, Netherlands)., (Thieme. All rights reserved.)

Rationale: Immune checkpoint inhibitor (ICI)-related pneumonitis is a serious autoimmune event affecting as many as 20% of patients with non-small-cell lung cancer (NSCLC), yet the factors underpinning its development in some patients and not others are poorly understood. Objectives: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. Methods: The study cohort consisted of patients with NSCLC who provided blood samples before and during ICI treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T-cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with NSCLC and patients with melanoma. Measurements and Main Results: Across both cohorts, patients in whom pneumonitis developed had higher pretreatment levels of immunoglobulin G autoantibodies targeting surfactant protein (SP)-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4 + IFN-γ-positive SP-B-specific T cells and expanding T-cell clonotypes recognizing this protein, accompanied by a proinflammatory serum proteomic profile. Conclusions: Our data suggest that the cooccurrence of SP-B-specific immunoglobulin G autoantibodies and CD4 + T cells is associated with the development of pneumonitis during ICI therapy. Pretreatment levels of these antibodies may represent a potential biomarker for an increased risk of developing pneumonitis, and on-treatment levels may provide a diagnostic aid.

Background: Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder, mostly and often firstly affecting the kidneys, together with impaired disharmonious growth and rickets, eventually resulting in progressive chronic kidney disease (CKD). With the introduction of cysteamine therapy, most pediatric patients reach adulthood with no need for kidney replacement therapy. Still, detailed changes in INC patients' clinical and morphological presentation over the past decades have not yet been thoroughly investigated., Methods: Two groups with a respective total of 64 children with INC and 302 children with CKD, both treated conservatively and aged 2 to 18 years, were prospectively observed in the time span from 1998 to 2022 with 1186 combined annual clinical and morphological examinations clustered into two measurement periods (1998 to 2015 and ≥ 2016)., Results: In INC patients, thoracic proportion indices remained markedly increased, whereas body fat stores remained decreased over the past 25 years (+ 1 vs. below ± 0 z-score, respectively). Their CKD peers presented with overall improved growth, general harmonization of body proportions, and improved body fat stores, while INC patients only presented with an isolated significant increase in leg length over time (∆0.36 z-score). eGFR adjusted for age did not significantly change over the past 25 years in both groups. Alkaline phosphatase (ALP) showed a significant decrease in CKD patients over time, while remaining above normal levels in INC patients., Conclusions: Disproportionate thoracic shape and impaired body fat stores remain the most characteristic morphological traits in INC patients over the past 25 years, while causal mechanisms remain unclear., (© 2024. The Author(s).)

A 14-day rat study with plasma metabolomics was conducted to evaluate the toxicity of Benzene. Wistar rats were orally administered Benzene daily at doses of 0, 300 and 1000 mg/kg bw. The study identified liver and kidneys as target organs of Benzene toxicity and found reductions in total white blood cells, absolute lymphocyte and eosinophil cell counts, and increased relative monocyte counts suggesting bone marrow as a target organ. The study also confirmed liver as a target organ using metabolomics, which showed indications of a stress reaction in rats and changes in metabolites suggestive of a metabolic disorder. The metabolomics investigations did not find any other toxicologically relevant modes of action, and the observed metabolite changes were not associated with markers for mitochondrial dysfunction. The study concludes that integration of omics technologies, such as metabolomics, in regulatory toxicity studies is possible, confirms existing knowledge and adds additional information that can be used for mechanistic understanding of observed toxicity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests Frank Faulhammer: is employed by BASF including stock ownership Bennard van Ravenzwaay: declares to have no known financial or personal relationships that could have appeared to influence the work reported in this paper A. Robert Schnatter: declares to have no known financial or personal relationships that could have appeared to influence the work reported in this paper Martijn Rooseboom: is employed by Shell including stock ownership Hennicke Kamp: is managing director of BASF Metabolome Solutions, a company that is offering metabolome analysis for various applications including toxicology research to external clients and BASF. He is employed by BASF including stock ownership Burkhard Flick: declares to have no known financial or personal relationships that could have appeared to influence the work reported in this paper Varun Giri: is employed by BASF including stock ownership Saskia Sperber: is employed by BASF including stock ownership Larry G Higgins and Michael G Penman: Penman Consulting provide consultancy services to the LOA REACH Consortium, and this article reflects the positions developed in the course of this work Neslihan Aygun Kocabas: is employed by TotalEnergies including stock ownership., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Preamble: Robotic magnetic navigation (RMN)-guided catheter ablation (CA) technology has been used for the treatment of cardiac arrhythmias for almost 20 years. Various studies reported that RMN allows for high catheter stability, improved lesion formation and a superior safety profile. So far, no guidelines or recommendations on RMN-guided CA have been published., Purpose: The aim of this consensus paper was to summarize knowledge and provide recommendations on management of arrhythmias using RMN-guided CA as treatment of atrial fibrillation (AF) and ventricular arrhythmias (VA)., Methodology: An expert writing group, performed a detailed review of available literature, and drawing on their own experience, drafted and voted on recommendations and summarized current knowledge and practice in the field. Recommendations on RMN-guided CA are presented in a guideline format with three levels of recommendations to serve as a reference for best practices in RMN procedures. Each recommendation is accompanied by supportive text and references. The various sections cover the practical spectrum from system and patient set-up, EP laboratory staffing, combination of RMN with fluoroscopy and mapping systems, use of automation features and ablation settings and targets, for different cardiac arrhythmias., Conclusion: This manuscript, presenting the combined experience of expert robotic users and knowledge from the available literature, offers a unique resource for providers interested in the use of RMN in the treatment of cardiac arrhythmias., Competing Interests: The Erasmus MC has received research grants from Acutus Medical, Biosense Webster and Stereotaxis. TS-T has received an educational grant from Abbott, a contract for education and advisory activities with Biotronik and consultancy contract with Acutus Medical and Ablacon. SW has received honoraria from Biotronik en Daiichi Sankyo. S-CY has received a research grant from Medtronic and honoraria from Medtronic and Boston Scientific. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Noten, Szili-Torok, Ernst, Burkhardt, Cavaco, Chen, Cheung, de Chillou, Crystal, Cooper, Gasparini, Geczy, Goehl, Hügl, Jin, Kampus, Kazemian, Khan, Kongstad, Magga, Peress, Raatikainen, Romanov, Rossvoll, Singh, Vatasescu, Wijchers, Yamashiro, Yap and Weiss.)

Grasspea (Lathyrus sativus L.) is an underutilised but promising legume crop with tolerance to a wide range of abiotic and biotic stress factors, and potential for climate-resilient agriculture. Despite a long history and wide geographical distribution of cultivation, only limited breeding resources are available. This paper reports a 5.96 Gbp genome assembly of grasspea genotype LS007, of which 5.03 Gbp is scaffolded into 7 pseudo-chromosomes. The assembly has a BUSCO completeness score of 99.1% and is annotated with 31719 gene models and repeat elements. This represents the most contiguous and accurate assembly of the grasspea genome to date., (© 2024. The Author(s).)

The habitat suitability for pollinators is an important factor for biodiversity and crop-based ecosystem services. Most flowering plants, including wild plants, rely on pollination ecosystem services for fructification and reproduction. Suitable nesting sites and accessible floral food resources are crucial to the abundance of pollinator insects. Therefore, the suitability for pollinators and the pollination service itself are influenced by the type of land use, the composition of the land cover and structures in the landscape. One way to estimate pollinator habitat suitability is to use computer models such as ESTIMAP and InVEST. Both models calculate the habitat suitability based on spatial land use data and their suitability as nesting and feeding habitats. Besides the decision for a model, the selected spatial dataset also has important effects on the modelling results. In Germany, a large number of Land Use and Land Cover (LULC) datasets is available, such as the European CORINE Land Cover, CORINE Urban Atlas, Biotope types, ATKIS or Open Street Map. These datasets differ in terms of spatial and thematic resolutions, LULC types, and abundance of structural elements, which are crucial input factors for modelling with ESTIMAP and InVEST. We applied and tested both models on the basis of two different datasets in the study area Hannover region in central Germany. A literature-based estimation and expert-based questionnaire determined the biophysical properties required for modelling with ESTIMAP and InVEST. The differences between the results based on two different spatial datasets and the differences between the models were estimated and the results that can be obtained by using freely available data were investigated and compared with the results based on non-publicly available data. The comparison of the results shows that the proportion of near-natural structures in the landscape are a decisive factor for modelling results. The comparison of the models shows that ESTIMAP estimates a higher influence of small structures in the landscape than InVEST, resulting in a higher pollinator habitat suitability. The median similarity index of the two models is between 0.68 to 0.93 for the highly detailed biotope type dataset and 0.40 to 0.79 for the less detailed Corine dataset. The results provide a guidance on how to choose the appropriate model and data to assess pollination ecosystem services., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hinsch et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To evaluate the impact of video sequences (cine-loops) on the interobserver agreement (IOA) using risk stratification systems (RSSs) for thyroid nodules (TNs)., Methods: Twenty TNs were randomly selected from a large database and evaluated by twelve experienced observers using five different RSSs (Kwak-, ACR-, EU-, Korean-TIRADS, ATA Guidelines). In the first step, the evaluation was conducted based on static ultrasound (US) images in two planes ("static"). Six months later, these cases were reevaluated by the same observers using video sequences in two planes ("cine-loops"). Fleiss' kappa (κ) was calculated for the IOA analyses., Results: IOA on static was moderate with κ values of 0.46, 0.42, 0.40, 0.45, and 0.38 for the Kwak-, ACR-, EU-, Korean-TIRADS, and ATA Guidelines, respectively, while the IOA on cine-loops was fair with κ values of 0.41, 0.38, 0.37, 0.36, and 0.34 for the Kwak-, ACR-, EU-, Korean-TIRADS, and ATA Guidelines, respectively. The overall IOA was superior in static images versus cine-loops ( p = 0.024). Among other findings, the subgroup analyses (related to age, gender, US certificates, number of thyroid US per week, and RSSs experience) particularly showed that the experience of the observers in using RSSs had a significant influence on the IOA., Conclusions: The overall IOA (all twelve observers and all five RSSs) was superior on static US images in comparison to cine-loops. Furthermore, the overall IOA of the five US features revealed superior κ values of the static images over cine-loops. However, this impact was significantly lower when the observers were highly experienced in the use of US RSSs of TNs.

Objective: The aim of this study was to investigate the use of image-guided volumetry in cerebellar infarction during the decision-making process for surgery. Particular emphasis was placed on the ratio of the infarction volume to the cerebellar volume or cranial posterior fossa volume. Methods: A retrospective, multicenter, multidisciplinary study design was selected. Statistical methods such as regression analysis and ROC analysis included the volumetric data of the infarction, the posterior fossa and the cerebellum itself as new factors. Results: Thirty-eight patients (mean age 75 (SD: 13.93) years, 16 (42%) female patients) were included. The mean infarction volume was 37.79 (SD: 25.24) cm 3 . Patients treated surgically had a 2.05-fold larger infarction than those managed without surgery ( p ≤ 0.001). Medical and surgical treatment revealed a significant difference in the ratio of the cranial posterior fossa volume to the infarction volume (medical 12.05, SD:9.09; surgical 5.14, SD: 5,65; p ≤ 0.001) and the ratio of the cerebellar volume to the infarction volume (medical 8.55, SD: 5.97; surgical 3.82, SD: 3.39; p ≤ 0.001). Subsequent multivariate regression analysis for surgical therapy showed significant results only for the posterior fossa volume to infarction volume ratio ≤/> 4:1 (OR: 1.162, CI: 1.007-1.341, p = 0.04). Younger (≤60 years) patients also had a significantly better outcome at discharge ( p ≤ 0.017). A cut-off value for the infarction volume of 31.35 cm 3 (sensitivity = 0.875, specificity = 0.2) was determined for the necessity of surgery. Conclusions: Volumetric data on the infarction, the posterior fossa and the cerebellum itself could be meaningful in decision-making towards surgery.

This work concerns a synthesis method for efficiently luminescent LuPO 4 :Eu 3+ nanoscale particles (∼100 nm) as well as their temperature (77-500 K) and time dependent photoluminescence. In addition, the incubation of these particles into cells of a human lung adenocarcinomic cell line A549 is briefly presented. This points to the application for bioimaging and detection of cancer cells in the field of medical diagnostics. The emission spectra of Eu 3+ doped LuPO 4 nanoparticles show four [Xe]4f 6 → [Xe]4f 6 transition multiplets between 580 and 720 nm, which are typically for Eu 3+ comprising luminescent materials, however the most intense one is the 5 D 0 → 7 F 4 (696.40 nm, 1.78 eV) transition due to the crystallographic position point symmetry D 2d of Eu 3+ in xenotime LuPO 4 . Such an Eu 3+ spectrum is rather useful for diagnostics due to the high penetration depth of 700 nm radiation into tissue., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Objectives: To resolve the epidemiology of airway infections with Burkholderia cepacia complex (Bcc) in patients with cystic fibrosis (pwCFs) over 40 years at a single treatment center., Methods: All Bcc and Burkholderia gladioli airway isolates were collected from pwCFs who presented at the cystic fibrosis outpatient and the lung transplantation clinics from 1983 to 2022., Results: The collection of 1205 strains is dominated by B. multivorans (56%), followed by B. cenocepacia (16%), B. stabilis (10%), and B. orbicola (9%). A total of 27 pwCFs experienced a single self-limiting episode of airway infection with Bcc. A total of 13 pwCFs were harboring Bcc for 1.7-13.6 years and 15 pwCFs were persistently infected with Bcc. A total of 16 Bcc-positive pwCFs received a lung transplant. Fatal post-transplant sepsis happened in one patient with B. multivorans, two with B. cenocepacia, and two with B. orbicola., Conclusions: After the first acquisition of Bcc, transient carriage was 2.7 times more frequent than persistent colonization. Infections with B. cenocepacia or B. orbicola confer a higher risk for post-transplant sepsis than an infection with B. multivorans., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)