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Microplastics (MPs) in agricultural plastic film mulching system changes microbial functions and nutrient dynamics in soils. However, how biodegradable MPs impact the soil gross nitrogen (N) transformations and crop N uptake remain significantly unknown. In this study, we conducted a paired labeling 15 N tracer experiment and microbial N-cycling gene analysis to investigate the dynamics and mechanisms of soil gross N transformation processes in soils amended with conventional (polyethylene, PE) and biodegradable (polybutylene adipate co-terephthalate, PBAT) MPs at concentrations of 0 %, 0.5 %, and 2 % (w/w). The biodegradable MPs-amended soils showed higher gross N mineralization rates (0.5-16 times) and plant N uptake rates (16-32 %) than soils without MPs (CK) and with conventional MPs. The MPs (both PE and PBAT) with high concentration (2 %) increased gross N mineralization rates compared to low concentration (0.5 %). Compare to CK, MPs decreased the soil gross nitrification rates, except for PBAT with 2 % concentration; while PE with 0.5 % concentration and PBAT with 2 % concentration increased but PBAT with 0.5 % concentration decreased the gross N immobilization rates significantly. The results indicated that there were both a concentration effect and a material effect of MPs on soil gross N transformations. Biodegradable MPs increased N-cycling gene abundance by 60-103 %; while there was no difference in the abundance of total N-cycling genes between soils without MPs and with conventional MPs. In summary, biodegradable MPs increased N cycling gene abundance by providing enriched nutrient substrates and enhancing microbial biomass, thereby promoting gross N transformation processes and maize N uptake in short-term. These findings provide insights into the potential consequences associated with the exposure of biodegradable MPs, particularly their impact on soil N cycling processes., Competing Interests: Declaration of Competing Interest This manuscript has not been published before nor submitted to another journal for the consideration of publication. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Aim: Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation. PITX2 is restricted to left atrial cardiomyocytes in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy and atrial fibrillation are not fully understood., Methods and Results: To identify mechanisms linking PITX2 deficiency to atrial fibrillation, we generated and characterized PITX2-deficient human atrial cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganised sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared to the control. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with atrial fibrillation compared to 43 patients in sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria., Conclusions: In summary, PITX2 deficiency causes mitochondrial dysfunction and a metabolic shift to glycolysis in human atrial cardiomyocytes. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Thermoelectric textile devices represent an intriguing avenue for powering wearable electronics. The lack of air-stable n-type polymers has, until now, prevented the development of n-type multifilament yarns, which are needed for textile manufacturing. Here, the thermomechanical properties of the recently reported n-type polymer poly(benzodifurandione) (PBFDO) are explored and its suitability as a yarn coating material is assessed. The outstanding robustness of the polymer facilitates the coating of silk yarn that, as a result, displays an effective bulk conductivity of 13 S cm -1 , with a projected half-life of 3.2 ± 0.7 years at ambient conditions. Moreover, the n-type PBFDO coated silk yarn with a Young's modulus of E = 0.6 GPa and a strain at break of ε break = 14% can be machine washed, with only a threefold decrease in conductivity after seven washing cycles. PBFDO and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) coated silk yarns are used to fabricate two out-of-plane thermoelectric textile devices: a thermoelectric button and a larger thermopile with 16 legs. Excellent air stability is paired with an open-circuit voltage of 17 mV and a maximum output power of 0.67 µW for a temperature difference of 70 K. Evidently, PBFDO coated multifilament silk yarn is a promising component for the realization of air stable thermoelectric textile devices., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Machine learning and robotics technologies are increasingly being used in the healthcare domain to improve the quality and efficiency of surgeries and to address challenges such as staff shortages. Robotic scrub nurses in particular offer great potential to address staff shortages by assuming nursing tasks such as the handover of surgical instruments., Methods: We introduce a robotic scrub nurse system designed to enhance the quality of surgeries and efficiency of surgical workflows by predicting and delivering the required surgical instruments based on real-time laparoscopic video analysis. We propose a three-stage deep learning architecture consisting of a single frame-, temporal multi frame-, and informed model to anticipate surgical instruments. The anticipation model was trained on a total of 62 laparoscopic cholecystectomies., Results: Here, we show that our prediction system can accurately anticipate 71.54% of the surgical instruments required during laparoscopic cholecystectomies in advance, facilitating a smoother surgical workflow and reducing the need for verbal communication. As the instruments in the left working trocar are changed less frequently and according to a standardized procedure, the prediction system works particularly well for this trocar., Conclusions: The robotic scrub nurse thus acts as a mind reader and helps to mitigate staff shortages by taking over a great share of the workload during surgeries while additionally enabling an enhanced process standardization., (© 2024. The Author(s).)

Background: Plant-based diets (PBDs) and planetary-health diets (PHDs) are recommended for their potential health and environmental benefits, but population-based evidence in diverse cultures is scarce., Methods: We included 9364 adults aged 45 years and older (52·3% female, 47·7% male) from the open cohort of the China Health and Nutrition Survey. Dietary intake was assessed using 3-day 24 h dietary recalls combined with weighing methods from 1997 to 2011, and mortality was documented from 1997 to 2015. We calculated the overall PBD index (PDI), healthful PBD index (hPDI), and unhealthful PBD index (uPDI; ranges 18-90), and the PHD score (range 0-140). We also estimated the related greenhouse gas emissions, land appropriation, and total water footprint and examined their associations with mortality., Findings: PBD indices were inversely related to greenhouse gas emissions, land appropriation, and total water footprint, whereas higher PHD score was related to higher environmental burdens (p<0·0001). During follow-up (mean 9·2 years), 792 (8·5%) death cases were documented. PDI (HR 1·08 [95% CI 0·88-1·32]) and hPDI (0·98 [0·80-1·21]) were not significantly associated with mortality, whereas higher uPDI was related to a higher mortality risk (1·55 [1·26-1·91]). In contrast, higher PHD score was associated with lower mortality risk (0·79 [0·63-0·99])., Interpretation: The PBDs showed environmental benefits, but are not necessarily associated with lower mortality risk. The PHD, developed mainly in western populations, was related to lower mortality risk but higher environmental burdens in the Chinese population., Funding: Fundamental Research Funds for the Central Universities, Zhejiang University Global Partnership Fund, and National Natural Science Foundation of China., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Importance: Atrial fibrillation (AF) has a substantial genetic component. The importance of polygenic risk is well established, while the contribution of rare variants to disease risk warrants characterization in large cohorts., Objective: To identify rare predicted loss-of-function (pLOF) variants associated with AF and elucidate their role in risk of AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS)., Design, Setting, and Participants: This was a genetic association and nested case-control study. The impact of rare pLOF variants was evaluated on the risk of incident AF. HF and CM were assessed in cause-specific Cox regressions. End of follow-up was July 1, 2022. Data were analyzed from January to October 2023. The UK Biobank enrolled 502 480 individuals aged 40 to 69 years at inclusion in the United Kingdom between March 13, 2006, and October 1, 2010. UK residents of European ancestry were included. Individuals with prior diagnosis of AF were excluded from analyses of incident AF., Exposures: Rare pLOF variants and an AF PRS., Main Outcomes and Measures: Risk of AF and incident HF or CM prior to and subsequent to AF diagnosis., Results: A total of 403 990 individuals (218 489 [54.1%] female) with a median (IQR) age of 58 (51-63) years were included; 24 447 were diagnosed with incident AF over a median (IQR) follow-up period of 13.3 (12.4-14.0) years. Rare pLOF variants in 6 genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) were associated with AF. Of these, TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicated in an external cohort. Combined with high PRS, rare pLOF variants conferred an odds ratio of 7.08 (95% CI, 6.03-8.28) for AF. Carriers with high PRS also had a substantial 10-year risk of AF (16% in female individuals and 24% in male individuals older than 60 years). Rare pLOF variants were associated with increased risk of CM both prior to AF (hazard ratio [HR], 3.13; 95% CI, 2.24-4.36) and subsequent to AF (HR, 2.98; 95% CI, 1.89-4.69)., Conclusions and Relevance: Rare and common genetic variation were associated with an increased risk of AF. The findings provide insights into the genetic underpinnings of AF and may aid in future genetic risk stratification.

This review addresses key findings on loneliness from the social, neurobiological and clinical fields. From a translational perspective, results from studies in humans and animals are included, with a focus on social interaction, mental and physical illness and the role of oxytocin in loneliness. In terms of social interactions, lonely individuals tend to exhibit a range of abnormal behaviors based on dysfunctional social cognitions that make it difficult for them to form meaningful relationships. Neurobiologically, a link has been established between loneliness and the hypothalamic peptide hormone oxytocin. Since social interactions and especially social touch regulate oxytocin signaling, lonely individuals may have an oxytocin imbalance, which in turn affects their health and well-being. Clinically, loneliness is a predictor of physical and mental illness and leads to increased morbidity and mortality. There is evidence that psychopathology is both a cause and a consequence of loneliness. The final section of this review summarizes the findings from social, neurobiological and clinical perspectives to present a new model of the complex construct of loneliness., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The angiotensin converting enzyme 2 (ACE2) plays a regulatory role in the cardiovascular system and serves SARS-CoV-2 as an entry receptor. The aim of this study was to synthesize and evaluate radiofluorinated derivatives of the ACE2 inhibitor MLN-4760. [ 18 F]F-MLN-4760 and [ 18 F]F-Aza-MLN-4760 were demonstrated to be suitable for non-invasive imaging of ACE2, potentially enabling a better understanding of its expression dynamics., Methods: Computational molecular modeling, based on the structures of human ACE2 (hACE2) and mouse ACE2 (mACE2), revealed that the ACE2-binding modes of F-MLN-4760 and F-Aza-MLN-4760 were similar to that of MLN-4760. Co-crystallization of the hACE2/F-MLN-4760 protein complex was performed for confirmation. Displacement experiments using [ 3 H]MLN-4760 enabled the determination of the binding affinities of the synthesized F-MLN-4760 and F-Aza-MLN-4760 to hACE2 expressed in HEK-ACE2 cells. Aryl trimethylstannane-based and pyridine-based radiofluorination precursors were synthesized and used for the preparation of the respective radiotracers. [ 18 F]F-MLN-4760 and [ 18 F]F-Aza-MLN-4760 were evaluated with regard to the uptake in HEK-ACE2 and HEK-ACE cells and in vitro binding to tissue sections of HEK-ACE2 xenografts and normal organs of mice. Biodistribution and PET/CT imaging studies of [ 18 F]F-MLN-4760 and [ 18 F]F-Aza-MLN-4760 were performed using HEK-ACE2 and HEK-ACE xenografted nude mice., Results: Crystallography data revealed an equal hACE2-binding mode for F-MLN-4760 as previously found for MLN-4760. Moreover, computer-based modeling indicated that similar binding to hACE2 and mACE2 holds true for both, F-MLN-4760 and F-Aza-MLN-4760, as is the case for MLN-4760. The IC 50 values were three-fold and seven-fold higher for F-MLN-4760 and F-Aza-MLN-4760, respectively, than for MLN-4760. [ 18 F]F-MLN-4760 and [ 18 F]F-Aza-MLN-4760 were obtained in 1.4 ± 0.3 GBq and 0.5 ± 0.1 GBq activity with > 99% radiochemical purity in a 5.3% and 1.2% radiochemical yield, respectively. Uptake in HEK-ACE2 cells was higher for [ 18 F]F-MLN-4760 (67 ± 9%) than for [ 18 F]F-Aza-MLN-4760 (37 ± 8%) after 3-h incubation while negligible uptake was seen in HEK-ACE cells (< 0.3%). [ 18 F]F-MLN-4760 and [ 18 F]F-Aza-MLN-4760 accumulated specifically in HEK-ACE2 xenografts of mice (13 ± 2% IA/g and 15 ± 2% IA/g at 1 h p.i.) with almost no uptake observed in HEK-ACE xenografts (< 0.3% IA/g). This was confirmed by PET/CT imaging, which also visualized unspecific accumulation in the gall bladder and intestinal tract., Conclusion: Both radiotracers showed specific and selective binding to ACE2 in vitro and in vivo. [ 18 F]F-MLN-4760 was, however, obtained in higher yields and the ACE2-binding affinity was superior over that of [ 18 F]F-Aza-MLN-4760. [ 18 F]F-MLN-4760 would, thus, be the candidate of choice for further development in view of its use for PET imaging of ACE2., (© 2024. The Author(s).)

Azole antifungals inhibit the sterol C14-demethylase (CYP51/Erg11) of the ergosterol biosynthesis pathway. Here we show that the azole-induced synthesis of fungicidal cell wall carbohydrate patches in the pathogenic mold Aspergillus fumigatus strictly correlates with the accumulation of the CYP51 substrate eburicol. A lack of other essential ergosterol biosynthesis enzymes, such as sterol C24-methyltransferase (Erg6A), squalene synthase (Erg9) or squalene epoxidase (Erg1) does not trigger comparable cell wall alterations. Partial repression of Erg6A, which converts lanosterol into eburicol, increases azole resistance. The sterol C5-desaturase (ERG3)-dependent conversion of eburicol into 14-methylergosta-8,24(28)-dien-3β,6α-diol, the "toxic diol" responsible for the fungistatic activity against yeasts, is not required for the fungicidal effects in A. fumigatus. While ERG3-lacking yeasts are azole resistant, ERG3-lacking A. fumigatus becomes more susceptible. Mutants lacking mitochondrial complex III functionality, which are much less effectively killed, but strongly inhibited in growth by azoles, convert eburicol more efficiently into the supposedly "toxic diol". We propose that the mode of action of azoles against A. fumigatus relies on accumulation of eburicol which exerts fungicidal effects by triggering cell wall carbohydrate patch formation., (© 2024. The Author(s).)

Background: Post-cardiac arrest syndrome (PCAS) after out-of-hospital cardiac arrest (OHCA) poses significant challenges due to its complex pathomechanisms involving inflammation, ischemia, and reperfusion injury. The identification of early available prognostic indicators is essential for optimizing therapeutic decisions and improving patient outcomes., Methods: In this retrospective single-center study, we analyzed real-world data from 463 OHCA patients with either prehospital or in-hospital return of spontaneous circulation (ROSC), treated at the Cardiac Arrest Center of the University Hospital of Marburg (MCAC) from January 2018 to December 2022. We evaluated demographic, prehospital, and clinical variables, including initial rhythms, resuscitation details, and early laboratory results. Statistical analyses included logistic regression to identify predictors of survival and neurological outcomes., Results: Overall, 46.9% (n = 217) of patients survived to discharge, with 70.1% (n = 152) achieving favorable neurological status (CPC 1 or 2). Age, initial shockable rhythm, resuscitation time to return of spontaneous circulation (ROSC), and early laboratory parameters like lactate, C-reactive protein, and glomerular filtration rate were identified as independent and combined Early Predictors of Outcome and Survival (EPOS), with high significant predictive value for survival (AUC 0.86 [95% CI 0.82-0.89]) and favorable neurological outcome (AUC 0.84 [95% CI 0.80-0.88])., Conclusion: Integration of EPOS into clinical procedures may significantly improve clinical decision making and thus patient prognosis in the early time-crucial period after OHCA. However, further validation in other patient cohorts is needed., Competing Interests: JK received research funding from CytoSorbents; BM received research funding from Abiomed; JK, GC, BS, and BM receive speakers’ honoraria from Abiomed; JK and BM received speakers’ honoraria from Astra Zeneca, BS received speakers’ honoraria from Bayer and GSK. No other authors reported disclosures.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Julian Kreutz reports a relationship with Abiomed Europe GmbH that includes: speaking and lecture fees. Birgit Markus reports a relationship with Abiomed Europe GmbH that includes: funding grants and speaking and lecture fees. Georgios Chatzis reports a relationship with Abiomed Europe GmbH that includes: speaking and lecture fees. Bernhard Schieffer reports a relationship with Abiomed Europe GmbH that includes: speaking and lecture fees. Julian Kreutz reports a relationship with CytoSorbents Europe GmbH that includes: funding grants. Julian Kreutz reports a relationship with AstraZeneca that includes: speaking and lecture fees. Birgit Markus reports a relationship with AstraZeneca that includes: speaking and lecture fees. Bernhard Schieffer reports a relationship with Bayer AG that includes: speaking and lecture fees. Bernhard Schieffer reports a relationship with GSK that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Humans achieve skilled actions by continuously correcting for motor errors or perceptual misjudgments, a process called sensorimotor adaptation. This can occur with the actor both detecting (explicitly) and not detecting the error (implicitly). We investigated how the magnitude of a perturbation and the corresponding error signal each contribute to the detection of a size perturbation during interaction with real-world objects. Participants grasped cuboids of different lengths in a mirror-setup allowing us to present different sizes for seen and felt cuboids, respectively. Visuo-haptic size mismatches (perturbations) were introduced either abruptly or followed a sinusoidal schedule. These schedules dissociated the error signal from the visuo-haptic mismatch: Participants could fully adapt their grip and reduce the error when a perturbation was introduced abruptly and then stayed the same, but not with a constantly changing sinusoidal perturbation. We compared participants' performance in a two-alternative forced choice (2AFC) task where participants judged these mismatches, and modelled error-correction in grasping movements by looking at changes in maximum grip apertures, measured using motion tracking. We found similar mismatch-detection performance with sinusoidal perturbation schedules and the first trial after an abrupt change, but decreasing performance over further trials for the latter. This is consistent with the idea that reduced error signals following adaptation make it harder to detect perturbations. Error-correction parameters indicated stronger error-correction in abruptly introduced perturbations. However, we saw no correlation between error-correction and overall mismatch-detection performance. This emphasizes the distinct contributions of the perturbation magnitude and the error signal in helping participants detect sensory perturbations., (© 2024. The Author(s).)

Purpose: [ 177 Lu]Lu-DOTATATE is an established somatostatin receptor (SSTR) agonist for the treatment of metastasized neuroendocrine neoplasms, while the SSTR antagonist [ 177 Lu]Lu-DOTA-LM3 has only scarcely been employed in clinics. Impressive preclinical data obtained with [ 161 Tb]Tb-DOTA-LM3 in tumor-bearing mice indicated the potential of terbium-161 as an alternative to lutetium-177. The aim of the present study was to compare the tolerability of 161 Tb- and 177 Lu-based DOTA-LM3 and DOTATATE in immunocompetent mice., Methods: Dosimetry calculations were performed based on biodistribution data of the radiopeptides in immunocompetent mice. Treatment-related effects on blood cell counts were assessed on Days 10, 28 and 56 after application of [ 161 Tb]Tb-DOTA-LM3 or [ 161 Tb]Tb-DOTATATE at 20 MBq per mouse. These radiopeptides were also applied at 100 MBq per mouse and the effects compared to those observed after application of the 177 Lu-labeled counterparts. Bone marrow smears, blood plasma parameters and organ histology were assessed at the end of the study., Results: The absorbed organ dose was commonly higher for the SSTR antagonist than for the SSTR agonist and for terbium-161 over lutetium-177. Application of a therapeutic activity level of 20 MBq [ 161 Tb]Tb-DOTA-LM3 or [ 161 Tb]Tb-DOTATATE was well tolerated without major hematological changes. The injection of 100 MBq of the 161 Tb- and 177 Lu-based somatostatin analogues affected the blood cell counts, however. The lymphocytes were 40-50% lower in treated mice compared to the untreated controls on Day 10 irrespective of the radionuclide employed. At the same timepoint, thrombocyte and erythrocyte counts were 30-50% and 6-12% lower, respectively, after administration of the SSTR antagonist (p < 0.05) while changes were less pronounced in mice injected with the SSTR agonist. All blood cell counts were in the normal range on Day 56. Histological analyses revealed minimal abnormalities in the kidneys, liver and spleen of treated mice. No correlation was observed between the organ dose and frequency of the occurrence of abnormalities., Conclusion: Hematologic changes were more pronounced in mice treated with the SSTR antagonist than in those treated with the SSTR agonist. Despite the increased absorbed dose delivered by terbium-161 over lutetium-177, [ 161 Tb]Tb-DOTA-LM3 and [ 161 Tb]Tb-DOTATATE should be safe at activity levels that are recommended for their respective 177 Lu-based analogues., (© 2024. The Author(s).)

Background: Cardiogenic shock (CS) following an out-of-hospital cardiac arrest (OHCA) poses significant management challenges, exacerbated by inflammatory responses and infectious complications. This study investigates the microbiological profiles and impacts of mechanical circulatory support (MCS) on inflammation and infection in OHCA patients. Methods: We retrospectively analyzed microbiological data from various specimens of 372 OHCA patients, who were treated at the Cardiac Arrest Center of the University Hospital of Marburg from January 2018 to December 2022. Clinical outcomes were evaluated to investigate the potential impact of MCS on infection and inflammation. Results: Of the study cohort, 115 patients received MCS. The microbiological analysis revealed a higher incidence of positive blood cultures in the MCS group vs. the non-MCS group (39% vs. 27.7%, p = 0.037), with predominantly Gram-positive bacteria. Patients with positive microbiological findings had longer in-hospital stays and prolonged periods of mechanical ventilation. The levels of inflammatory markers such as C-reactive protein (CRP) and procalcitonin (PCT) differed, suggesting a more pronounced inflammatory response in MCS patients, especially in the later ICU stages. Notably, despite the higher infection rate in the MCS group, the survival rates did not significantly differ in the two groups. Conclusions: MCS appears to influence the microbiological and inflammatory landscape in OHCA patients, increasing the susceptibility to certain infections but not affecting the overall mortality. This study underscores the complexity of managing post-resuscitation care and highlights the need for tailored therapeutic strategies to effectively mitigate infectious and inflammatory complications.

Dogs can discriminate stressed from non-stressed human odour samples, but the effect on their cognition is unstudied. Using a cognitive bias task, we tested how human odours affect dogs' likelihood of approaching a food bowl placed at three ambiguous locations ("near-positive", "middle" and "near-negative") between trained "positive" (rewarded) and "negative" (unrewarded) locations. Using odour samples collected from three unfamiliar volunteers during stressful and relaxing activities, we tested eighteen dogs under three conditions: no odour, stress odour and relaxed odour, with the order of test odours counterbalanced across dogs. When exposed to stress odour during session three, dogs were significantly less likely to approach a bowl placed at one of the three ambiguous locations (near-negative) compared to no odour, indicating possible risk-reduction behaviours in response to the smell of human stress. Dogs' learning of trained positive and negative locations improved with repeated testing and was significant between sessions two and three only when exposed to stress odour during session three, suggesting odour influenced learning. This is the first study to show that without visual or auditory cues, olfactory cues of human stress may affect dogs' cognition and learning, which, if true, could have important consequences for dog welfare and working performance., (© 2024. The Author(s).)

Introduction: Patients with progressing intrahepatic cholangiocarcinoma (iCCA) harboring an isocitrate dehydrogenase 1 (IDH1) mutation who received ivosidenib showed a median progression-free survival (PFS) benefit of 1.3 months compared to placebo in the phase 3 ClarIDHy trial., Case Presentations: We describe 2 consecutive patients with previously treated unresectable and metastatic iCCA harboring an IDH1 R132 mutation who achieved durable clinical responses with ivosidenib 500 mg once daily for >12 months until disease progression. In one case with a mixed response, a single progressive liver metastasis was additionally treated locally with interstitial brachytherapy, while ivosidenib was continued until further progression. Ivosidenib therapy resulted in long-term disease control with PFS of 20 and 13 months and duration of treatment of 26 and 13 months, respectively, with no relevant side effects., Conclusion: Patients with unresectable or metastatic IDH1-mutated iCCA can achieve sustained clinical responses for >12 months with ivosidenib. No new safety signals were observed during long-term treatment with ivosidenib., Competing Interests: C.M. and S.F. have no conflicts of interest to declare. T.R. is an employee of Servier Deutschland GmbH. V.K. received honoraria for speakers’ corner from AbbVie, Gilead, Falk, Albireo, and CSL Behring, and participated in an advisory board for AstraZeneca. M.V. received honoraria for speaker, consultancy, and advisory role from Servier, Roche, BMS, MSD, EISAI, Bayer, Lilly, AstraZeneca, Merck Serono, Sirtex, Ipsen, Nordic Pharma, and Amgen., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Several research groups have explored the potential of scandium radionuclides for theragnostic applications due to their longer half-lives and equal or similar coordination chemistry between their diagnostic and therapeutic counterparts, as well as lutetium-177 and terbium-161, respectively. Unlike the gallium-68/lutetium-177 pair, which may show different in-vivo uptake patterns, the use of scandium radioisotopes promises consistent behaviour between diagnostic and therapeutic radiopeptides. An advantage of scandium's longer half-life over gallium-68 is the ability to study radiopeptide uptake over extended periods and its suitability for centralized production and distribution. However, concerns arise from scandium-44's decay characteristics and scandium-43's high production costs. This study aimed to evaluate the dosimetric implications of using scandium radioisotopes with somatostatin analogues against gallium-68 for PET imaging of neuroendocrine tumours., Methods: Absorbed dose per injected activity (AD/IA) from the generated time-integrated activity curve (TIAC) were estimated using the radiopeptides [ 43/44/44m Sc]Sc- and [ 68 Ga]Ga-DOTATATE. The kidneys, liver, spleen, and red bone marrow (RBM) were selected for dose estimation studies. The EGSnrc and MCNP6.1 Monte Carlo (MC) codes were used with female (AF) and male (AM) ICRP phantoms. The results were compared to Olinda/EXM software, and the effective dose concentrations assessed, varying composition between the scandium radioisotopes., Results: Our findings showed good agreement between the MC codes, with - 3 ± 8% mean difference. Kidneys, liver, and spleen showed differences between the MC codes (min and max) in a range of - 4% to 8%. This was observed for both phantoms for all radiopeptides used in the study. Compared to Olinda/EXM the largest observed difference was for the RBM, of 21% for the AF and 16% for the AM for scandium- and gallium-based radiopeptides. Despite the differences, our findings showed a higher absorbed dose on [ 43/44 Sc]Sc-DOTATATE compared to its 68 Ga-based counterpart., Conclusion: This study found that [ 43/44 Sc]Sc-DOTATATE delivers a higher absorbed dose to organs at risk compared to [ 68 Ga]Ga-DOTATATE, assuming equal distribution. This is due to the longer half-life of scandium radioisotopes compared to gallium-68. However, calculated doses are within acceptable ranges, making scandium radioisotopes a feasible replacement for gallium-68 in PET imaging, potentially offering enhanced diagnostic potential with later timepoint imaging., (© 2024. The Author(s).)

Introduction: During the COVID-19 pandemic, single parents and their children were particularly exposed to stress due to the containment measures and to limited resources. We analyzed differences in the social and health situation of children and adolescents in one-parent households and two-parent households at the end of the pandemic., Methods: The analysis is based on data from the KIDA study, in which parents of 3‑ to 15-year-old children as well as 16- to 17-year-old adolescents were surveyed in 2022/2023 (telephone: n = 6992; online: n = 2896). Prevalences stratified by family type were calculated for the indicators psychosocial stress, social support, health, and health behavior. Poisson regressions were adjusted for gender, age, level of education, and household income., Results: Children and adolescents from one-parent households are more likely to be burdened by financial restrictions, family conflicts, and poor living conditions and receive less school support than peers from two-parent households. They are more likely to have impairments in health as well as increased healthcare needs, and they use psychosocial services more frequently. Furthermore, they are less likely to be active in sports clubs, but they take part in sporting activities at schools as often as minors from two-parent households. The differences are also evident when controlling for income and education., Discussion: Children and adolescents from one-parent households can be reached well through exercise programs in a school setting. Low-threshold offers in daycare centers, schools, and the community should therefore be further expanded. Furthermore, interventions are needed to improve the socioeconomic situation of single parents and their children., (© 2024. The Author(s).)

Background: Systemic sclerosis (SSc) is a rare chronic autoimmune disease with heterogeneous manifestations. In the last decade, several clinical trials have been conducted to evaluate new treatment options for SSc. The purpose of this work is to update the recommendations of the Brazilian Society of Rheumatology in light of the new evidence available for the pharmacological management of SSc., Methods: A systematic review including randomized clinical trials (RCTs) for predefined questions that were elaborated according to the Patient/Population, Intervention, Comparison, and Outcomes (PICO) strategy was conducted. The rating of the available evidence was performed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. To become a recommendation, at least 75% agreement of the voting panel was needed., Results: Six recommendations were elaborated regarding the pharmacological treatment of Raynaud's phenomenon, the treatment (healing) and prevention of digital ulcers, skin involvement, interstitial lung disease (ILD) and gastrointestinal involvement in SSc patients based on results available from RCTs. New drugs, such as rituximab, were included as therapeutic options for skin involvement, and rituximab, tocilizumab and nintedanib were included as therapeutic options for ILD. Recommendations for the pharmacological treatment of scleroderma renal crisis and musculoskeletal involvement were elaborated based on the expert opinion of the voting panel, as no placebo-controlled RCTs were found., Conclusion: These guidelines updated and incorporated new treatment options for the management of SSc based on evidence from the literature and expert opinion regarding SSc, providing support for decision-making in clinical practice., (© 2024. The Author(s).)

Purpose: Decision support systems and context-aware assistance in the operating room have emerged as the key clinical applications supporting surgeons in their daily work and are generally based on single modalities. The model- and knowledge-based integration of multimodal data as a basis for decision support systems that can dynamically adapt to the surgical workflow has not yet been established. Therefore, we propose a knowledge-enhanced method for fusing multimodal data for anticipation tasks., Methods: We developed a holistic, multimodal graph-based approach combining imaging and non-imaging information in a knowledge graph representing the intraoperative scene of a surgery. Node and edge features of the knowledge graph are extracted from suitable data sources in the operating room using machine learning. A spatiotemporal graph neural network architecture subsequently allows for interpretation of relational and temporal patterns within the knowledge graph. We apply our approach to the downstream task of instrument anticipation while presenting a suitable modeling and evaluation strategy for this task., Results: Our approach achieves an F1 score of 66.86% in terms of instrument anticipation, allowing for a seamless surgical workflow and adding a valuable impact for surgical decision support systems. A resting recall of 63.33% indicates the non-prematurity of the anticipations., Conclusion: This work shows how multimodal data can be combined with the topological properties of an operating room in a graph-based approach. Our multimodal graph architecture serves as a basis for context-sensitive decision support systems in laparoscopic surgery considering a comprehensive intraoperative operating scene., (© 2024. The Author(s).)

Background: This study investigated sex differences in acute myocarditis patients during index hospitalization., Methods: We included 365 patients with acute myocarditis, hospitalized with continuous monitoring at the intensive care unit from 2000-2023 into the Basel Myocarditis Cohort study. We compared sex differences in clinical presentation, the presenting electrocardiogram, prior medical history, inflammatory and cardiac biomarkers, cardiac imaging, arrhythmia occurrence, and short- to midterm outcomes., Results: Mean age was 41.3 years, and 26.3% were female. Compared with men, women were older (median 49.7 vs 38.3 years, P < .001) at the time of diagnosis and presented more frequently with dyspnea (41 vs 26%, P = .013) and a higher Killip class (P = .011). In the presenting electrocardiogram, men had a higher occurrence of diffuse ST-elevation (38 vs 9%, P < .001) and PQ-depression (31 vs 20%, P = .042), compared with women. Women had higher N-terminal pro B-type natriuretic peptide levels (1180 vs 387 ng/L, P = .015), lower cardiac troponin T levels (389 vs 726 ng/L, P = .006), and fewer segments with nonischemic late gadolinium enhancement on cardiac magnetic resonance imaging (1 vs 3, P = .005), but similar left ventricular ejection fraction (55 vs 55%, P = .629), compared with men. Overall, hospital stay was longer in women compared with men (7 vs 5 days, P = .018), with a similar length of intensive care unit stay (2.6 vs 2.7 days, P = .922). Women more often developed severe arrhythmia (8.3 vs 2.2%, P = .015) and heart failure during the hospitalization (31.3 vs 16.4%, P = .003)., Conclusion: Compared with men, women with acute myocarditis were older at the time of diagnosis, presented more often with heart failure, and had an increased frequency of severe arrhythmia., (Copyright © 2024 Elsevier Inc. All rights reserved.)

(1) Background: The role of selenium in cancer biology remains poorly understood. Our aim was to study the course of selenium serum levels and the use of selenium supplements during breast cancer therapy. (2) Methods: Serum selenium levels, clinical-pathological data, selenium supplementation, and lifestyle factors were monitored quarterly over one year. (3) Results: A total of 110 non-metastatic breast cancer patients were enrolled in the prospective observational "BEGYN-1" study. At baseline, 2.9% of patients were selenium-deficient (<50 ng/mL), 1.9% were overdosed (>120 ng/mL), and 6.4% received substitution. The median selenium level was 81.5 ng/mL and ranged between 78.7 and 84.5 ng/mL within the year. A total of 25.3% of the patients received supplementation, resulting in significantly higher selenium levels ( p < 0.05). A total of 8.7-28.6% of the patients using supplements were overdosed. Selenium levels strongly correlated with mushroom consumption ( p = 0.003), but no association was found with therapy or clinical characteristics. (4) Conclusions: Although selenium deficiency is rare, serum selenium levels should be assessed in breast cancer patients. Mushrooms and nuts should be preferred over supplements to correct selenium deficiency. Ruling out selenium deficiency helps prevent the risk of selenosis and avoid unnecessary, costly supplementation in patients who are often financially burdened due to their disease.

Microbial inoculation involves transplanting microorganisms from their natural habitat to new plants or soils to improve plant performance, and it is being increasingly used in agriculture and ecological restoration. However, microbial inoculants can invade and alter the composition of native microbial communities; thus, a comprehensive analysis is urgently needed to understand the overall impact of microbial inoculants on the biomass, diversity, structure and network complexity of native communities. Here we provide a meta-analysis of 335 studies revealing a positive effect of microbial inoculants on soil microbial biomass. This positive effect was weakened by environmental stress and enhanced by the use of fertilizers and native inoculants. Although microbial inoculants did not alter microbial diversity, they induced major changes in the structure and bacterial composition of soil microbial communities, reducing the complexity of bacterial networks and increasing network stability. Finally, higher initial levels of soil nutrients amplified the positive impact of microbial inoculants on fungal biomass, actinobacterial biomass, microbial biomass carbon and microbial biomass nitrogen. Together, our results highlight the positive effects of microbial inoculants on soil microbial biomass, emphasizing the benefits of native inoculants and the important regulatory roles of soil nutrient levels and environmental stress., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Homobimetallic dimetallocenes exhibiting two identical metal atoms sandwiched between two η 5 bonded cyclopentadienyl rings is a narrow class of compounds, with representative examples being dizincocene and diberyllocene. Here we report the synthesis and structural characterization of a heterobimetallic dimetallocene, accessible through heterocoupling of lithium and aluminylene fragments with pentaisopropylcyclopentadienyl ligands. The Al-Li bond features a high ionic character and profits from attractive dispersion interactions between the isopropyl groups of the cyclopentadienyl ligands. A key synthetic step is the isolation of a cyclopentadienylaluminylene monomer, which also enables the structural characterization of this species. In addition to their structural authentication by single-crystal X-ray diffraction analysis, both compounds were characterized by multinuclear NMR spectroscopy in solution and in the solid state. Furthermore, reactivity studies of the lithium-aluminium heterobimetallic dimetallocene with an N-heterocyclic carbene and different heteroallenes were performed and show that the Al-Li bond is easily cleaved., (© 2024. The Author(s).)

Background and Objective: Prostate-specific antigen (PSA) levels in midlife are strongly associated with the long-term risk of lethal prostate cancer in cohorts not subject to screening. This is the first study evaluating the association between PSA levels drawn as part of routine medical care in the Norwegian population and prostate cancer incidence and mortality. The objective of the study was to determine the association between midlife PSA levels <4.0 ng/ml, drawn aspart of routine medical care, and long-term risk of prostate cancer death., Methods: The Norwegian Prostate Cancer Consortium collected >8 million PSA results from >1 million Norwegian males (more than or equal to) 40 yr of age. We studied 176 099 men (predefined age strata: 40-54 and 55-69 yr) without a prior prostate cancer diagnosis who had a nonelevated baseline PSA level (<4.0 ng/ml) between January 1,1995 and December 31, 2005. We assessed the 16-yr risk of prostate cancer mortality. We calculated the discrimination (C-index) between predefined PSA strata (<0.5, 0.5-0.9, 1.0-1.9, 2.0-2.9, and 3.0-3.9 ng/ml) and subsequent prostate cancer death. Survival curves were plotted using the Kaplan-Meier method., Key Findings and Limitations: The median follow-up time of men who did not get prostate cancer was 17.9 yr. Overall, 84% of men had a baseline PSA level of <2.0 ng/ml and 1346 men died from prostate cancer, with 712 deaths (53%) occurring in the 16% of men with the highest baseline PSA of 2.0-3.9 ng/ml. Baseline PSA levels were associated with prostate cancer mortality (C-index 0.72 for both age groups, 40-54 and 55-69 yr). The fact that the reason for any given PSA measurement remains unknown represents a limitation., Conclusions and Clinical Implications: We replicated prior studies that baseline PSA at age 40-69 yr can be used to stratify a man's risk of dying from prostate cancer within the next 15-20 yr., Patient Summary: A prostate-specific antigen level obtained as part of routine medical care is strongly associated with a man's risk of dying from prostate cancer in the next two decades., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Patients with atrial fibrillation (AF) are at increased risks of cardiovascular diseases and mortality, but risks according to age at diagnosis have not been reported. This study investigated age-specific risks of outcomes among patients with AF and the background population., Methods: This nationwide population-based cohort study included patients with AF and controls without outcomes by the application of exposure density matching on the basis of sex, year of birth, and index date. The absolute risks and hazard rates were stratified by age groups and assessed using competing risk survival analyses and Cox regression models, respectively. The expected differences in residual life years among participants were estimated., Results: The study included 216 579 AF patients from year 2000 to 2020 and 866 316 controls. The mean follow-up time was 7.9 years. Comparing AF patients with matched controls, the hazard ratios among individuals ≤50 years was 8.90 [95% confidence interval (CI), 7.17-11.0] for cardiomyopathy, 8.64 (95% CI, 7.74-9.64) for heart failure, 2.18 (95% CI, 1.89-2.52) for ischaemic stroke, and 2.74 (95% CI, 2.53-2.96) for mortality. The expected average loss of life years among individuals ≤50 years was 9.2 years (95% CI, 9.0-9.3) years. The estimates decreased with older age., Conclusions: The findings show that earlier diagnosis of AF is associated with a higher hazard ratio of subsequent myocardial disease and shorter life expectancy. Further studies are needed to determine causality and whether AF could be used as a risk marker among particularly younger patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Yaws, caused by Treponema pallidum ssp. pertenue, remains a significant public health concern in tropical regions of West Africa and the South Pacific, primarily affecting children in remote areas with limited access to hygiene and sanitation. In this study, conducted in three endemic countries of West Africa where yaws remains a significant public health concern (Ghana, Cameroon, and Côte d'Ivoire), we aimed to assess the knowledge, attitudes, and practices related to yaws among community members, community health workers (CHWs), and traditional healers. The study revealed variations in the perception of causes of yaws among community members: the majority or participants in Ghana attributed yaws to germs (60.2%); in Cameroon the most reported form of transmission was contact with or drinking infected water sources (44.6%); and in Côte d'Ivoire both of these answers were also the most prevalent (60.3% germs and 93.% water sources). A substantial proportion of participants in Côte d'Ivoire also associated yaws with witchcraft and divine punishment (44.8%). Only a small proportion of individuals in Ghana and Côte d'Ivoire correctly identified contact with an infected person as a form of transmission (11.9% and 20.7%, respectively) and less than half in Cameroon (42.6%), although more than 98% of all participants reported avoidance behaviours towards yaws infected people due to fear of getting infected. Most participants expressed a preference for seeking care at hospitals (49.2%, 60.6%, 86.2%) or health care professionals including doctors and nurses (58.5%, 41,5% and 17.2%) if they were diagnosed with yaws, although a quarter of participants in Côte d'Ivoire also sought support from traditional healers. The CHWs interviewed were generally well-trained on yaws causes and treatment options, although they often reported low availability of treatment and diagnostic tests for yaws. Our findings underscore the need for community education, awareness campaigns, ongoing CHW training, and improved access to yaws treatment and diagnostic resources. The data also suggest that collaboration with traditional healers, who usually hold a highly esteemed position in the society, such as giving training on yaws causes and transmission or exchanging knowledge on treatment options, could be beneficial in certain regions, particularly in Côte d'Ivoire., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Beiras 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.)

Dissemination of digital cognitive behavioural therapy is a promising approach for treating insomnia in the broad population. Current evidence supports the effectiveness of the digital format, but clinical findings are often limited by the choice of control group and lack of in-depth therapeutic measures. This study was designed to investigate the specific effects of digital cognitive behavioural therapy in comparison to a self-monitoring application. Participants meeting criteria for insomnia were randomly allocated (1:1) to 8 weeks of digital cognitive behavioural therapy or 8 weeks of digital sleep monitoring (control application). The primary outcome, insomnia severity, was assessed at baseline, 8- and 16-weeks post-randomisation. Secondary outcomes included the assessment of sleep via application-integrated sleep diaries and actigraphy. Linear-mixed models were fitted to assess between-group differences. Fifty-six participants (48 females, mean age: M = 45.55 ± 13.70 years) were randomised to either digital cognitive behavioural therapy (n = 29) or digital sleep monitoring (n = 27). At 8- and 16-weeks post-randomisation, large treatment effects (d = 0.87-1.08) indicated robust reductions (-3.70 and -2.97, respectively; p ≤ 0.003) in insomnia severity in the digital cognitive behavioural therapy arm, relative to digital sleep monitoring. Treatment effects in favour of digital cognitive behavioural therapy were also found for self-reported and actigraphy-derived sleep continuity variables, indicating that sleep improved throughout the 8-week intervention period. Our study reinforces the role of digital cognitive behavioural therapy in achieving clinical improvements for patients with insomnia, affirming previous findings and supporting the specific effects of cognitive behavioural therapy., (© 2024 The Author(s). Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Main Conclusion: We generated transplastomic tobacco lines that stably express a human Basic Fibroblast Growth Factor (hFGFb) in their chloroplasts stroma and purified a biologically active recombinant hFGFb. MAIN: The use of plants as biofactories presents as an attractive technology with the potential to efficiently produce high-value human recombinant proteins in a cost-effective manner. Plastid genome transformation stands out for its possibility to accumulate recombinant proteins at elevated levels. Of particular interest are recombinant growth factors, given their applications in animal cell culture and regenerative medicine. In this study, we produced recombinant human Fibroblast Growth Factor (rhFGFb), a crucial protein required for animal cell culture, in tobacco chloroplasts. We successfully generated two independent transplastomic lines that are homoplasmic and accumulate rhFGFb in their leaves. Furthermore, the produced rhFGFb demonstrated its biological activity by inducing proliferation in HEK293T cell lines. These results collectively underscore plastid genome transformation as a promising plant-based bioreactor for rhFGFb production., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Clinical assessment in emergency departments (EDs) for possible acute myocardial infarction (AMI) requires at least one cardiac troponin (cTn) blood test. The turn-around time from blood draw to posting results in the clinical portal for central laboratory analysers is ~1-2 hours. New generation, high-sensitivity, point-of-care cardiac troponin I (POC-cTnI) assays use whole blood on a bedside (or near bedside) analyser that provides a rapid (8 min) result. This may expedite clinical decision-making and reduce length of stay. Our purpose is to determine if utilisation of a POC-cTnI testing reduces ED length of stay. We also aim to establish an optimised implementation process for the amended clinical pathway., Methods and Analysis: This quality improvement initiative has a pragmatic multihospital stepped-wedge cross-sectional cluster randomised design. Consecutive patients presenting to the ED with symptoms suggestive of possible AMI and having a cTn test will be included. Clusters (comprising one or two hospitals each) will change from their usual-care pathway to an amended pathway using POC-cTnI-the 'intervention'. The dates of change will be randomised. Changes occur at 1 month intervals, with a minimum 2 month 'run-in' period. The intervention pathway will use a POC-cTnI measurement as an alternate to the laboratory-based cTn measurement. Clinical decision-making steps and logic will otherwise remain unchanged. The POC-cTnI is the Siemens (Erlangen Germany) Atellica VTLi high-sensitivity cTnI assay. The primary outcome is ED length of stay. The safety outcome is cardiac death or AMI within 30 days for patients discharged directly from the ED., Ethics and Dissemination: Ethics approval has been granted by the New Zealand Southern Health and Disability Ethics Committee, reference 21/STH/9. Results will be published in a peer-reviewed journal. Lay and academic presentations will be made. Māori-specific results will be disseminated to Māori stakeholders., Trial Registration Number: ACTRN12619001189112., Competing Interests: Competing interests: Siemens Healthcare had no part in the writing of the protocol, and will play no part in the data analysis, interpretation or writing of manuscripts. JWP reports consultancy with Upstream, Luminoma, Siemens Healthineers, Quidel Corporation and Radiometer Health. NM has received honoraria from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers and LumiraDx and the University of Edinburgh have received research grants from Siemens Healthineers and Abbott Diagnostics unrelated to this work. LC has received honoraria/speakers’ fees from Abbott Diagnostics, Beckman Coulter and Siemens Healthineers, and institutional research grants from Siemens Healthineers, Beckman Coulter and Abbott Diagnostics unrelated to this work. ASJ reports work with all major diagnostic companies. FP reports research grants with Brainbox, Quidel; Consultancies with Abbott, Brainbox, Instrument Labs, Janssen, Osler, Roche, Siemens, Spinchip, Vifor; Stock/Ownership Interests with AseptiScope, Brainbox, Braincheck, Coagulo, Comprehensive Research Associates LLC, Comprehensive Research Management, Emergencies in Medicine LLC, Fast, Forrest Devices, Ischemia DX LLC, Lucia, Prevencio, RCE Technologies, ROMTech, ScPharma, Trivirum, Upstream. MT has received honoraria and research funding from Abbott, Alere, Beckman, QuidelOrtho, Radiometer, Roche and Siemens., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Triazaphospholes are potential polydentate ligands due to the presence of both phosphorus and nitrogen donor atoms within the aromatic 5-membered heterocycle. The incorporation of an additional pyridyl-substituent opens up the possibility of a post-synthesis modification via chemoselective and also stepwise alkylation exclusively of the nitrogen atoms. This can be controlled by the choice and by the stoichiometry of the electrophile and allows the targeted synthesis of a variety of novel mono- and dicationic ligands. Reaction with Cu(I)-halides causes the formation of cuprates of the type [CuX n ] (n-1)- , which enables coordination of the π-acidic phosphorus donor to the negatively charged metal core, which is favored over the coordination by a strongly σ-donating nitrogen atom. The use of cationic triazaphosphole derivatives can be used as a strategy to enforce the coordination of the ligand to an electron rich metal solely via the phosphorus atom. However, there is a subtle balance between the formation of either coordination polymers or dimeric structures, as the substitution pattern on the heterocycle and the nature of the halide have a large influence on the coordination motifs formed., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Functionally relevant coronary artery disease (fCAD) can result in premature death or nonfatal acute myocardial infarction. Its early detection is a fundamentally important task in medicine. Classical detection approaches suffer from limited diagnostic accuracy or expose patients to possibly harmful radiation. Here we show how machine learning (ML) can outperform cardiologists in predicting the presence of stress-induced fCAD in terms of area under the receiver operating characteristic (AUROC: 0.71 vs. 0.64, p = 4.0E-13). We present two ML approaches, the first using eight static clinical variables, whereas the second leverages electrocardiogram signals from exercise stress testing. At a target post-test probability for fCAD of <15%, ML facilitates a potential reduction of imaging procedures by 15-17% compared to the cardiologist's judgement. Predictive performance is validated on an internal temporal data split as well as externally. We also show that combining clinical judgement with conventional ML and deep learning using logistic regression results in a mean AUROC of 0.74., (© 2024. The Author(s).)

Raphanus sativus L. is a potential source of raw material for biodiesel fuel due to the high oil content in its grains. In Brazil, this species is cultivated in the low rainfall off-season, which limits the productivity of the crop. The present study investigated the effects of water restriction on the physiological and biochemical responses, production components, and oil quality of R. sativus at different development stages. The treatments consisted of 100% water replacement (control), 66%, and 33% of field capacity during the phenological stages of vegetative growth, flowering, and grain filling. We evaluated characteristics of water relations, gas exchange, chlorophyll a fluorescence, chloroplast pigment, proline, and sugar content. The production components and chemical properties of the oil were also determined at the end of the harvest cycle. Drought tolerance of R. sativus was found to be mediated primarily during the vegetative growth stage by changes in photosynthetic metabolism, stability of photochemical efficiency, increased proline concentrations, and maintenance of tissue hydration. Grain filling was most sensitive to water limitation and showed a reduction in yield and oil content. However, the chemical composition of the oil was not altered by the water deficit. Our data suggest that R. sativus is a drought-tolerant species.

Objectives: Midostaurin is an oral multitargeted tyrosine kinase inhibitor for the treatment of acute myeloid leukemia (AML). Therapeutic drug monitoring of midostaurin may support its safe use when suspecting toxicity or combined with strong CYP3A4 inhibitors., Methods: A stable isotope dilution liquid chromatography-tandem mass spectrometry method was developed and validated for the determination and quantification of midostaurin in human plasma and serum. Midostaurin serum concentrations were analyzed in 12 patients with FMS-like tyrosine kinase 3 (FLT3)-mutated AML during induction chemotherapy with cytarabine, daunorubicin, and midostaurin. Posaconazole was used as prophylaxis of invasive fungal infections., Results: Linear quantification of midostaurin was demonstrated across a concentration range of 0.01-8.00 mg/L. Inter- and intraday imprecisions of the proposed method were well within ±10%. Venous blood samples were taken in nine and three patients in the first and second cycle of induction chemotherapy. Median (range) midostaurin serum concentration was 7.9 mg/L (1.5-26.1 mg/L) as determined in 37 independent serum specimens., Conclusion: In a real-life cohort of AML patients, interindividual variability in midostaurin serum concentrations was high, highlighting issues concerning optimal drug dosing in AML patients. A personalized dosage approach may maximize the safety of midostaurin. Prospective studies and standardization of analytical methods to support such an approach are needed., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Soil pollution by metals and metalloids as a consequence of anthropogenic industrialisation exerts a seriously damaging impact on ecosystems. However, certain plant species, termed hyperaccumulators, are able to accumulate extraordinarily high concentrations of these metal(loid)s in their aboveground tissues. Such hyperaccumulation of metal(loid)s is known to act as a defence against various antagonists, such as herbivores and pathogens. We investigated the influences of metal(loid)s on potential defence traits, such as foliar elemental, organic and mechanical defences, in the hyperaccumulator plant species Arabidopsis halleri (Brassicaceae) by artificially amending the soil with common metallic pollutants, namely cadmium (Cd) and zinc (Zn). Additionally, unamended and metal-amended soils were supplemented with the metalloid silicon (Si) to study whether Si could alleviate metal excess. Individuals originating from one non-/low- and two moderately to highly metal-contaminated sites with different metal concentrations (hereafter called accessions) were grown for eight weeks in a full-factorial design under standardised conditions. There were significant interactive effects of metal amendment and Si supplementation on foliar concentrations of certain elements (Zn, Si, aluminium (Al), iron (Fe), potassium (K) and sulfur (S), but these were accession-specific. Profiles of glucosinolates, characteristic organic defences of Brassicaceae, were distinct among accessions, and the composition was affected by soil metal amendment. Moreover, plants grown on metal-amended soil contained lower concentrations of total glucosinolates in one of the accessions, which suggests a potential trade-off between inorganic defence acquisition and biosynthesis of organic defence. The density of foliar trichomes, as a proxy for the first layer of mechanical defence, was also influenced by metal amendment and/or Si supplementation in an accession-dependent manner. Our study highlights the importance of examining the effects of co-occurring metal(loid)s in soil on various foliar defence traits in different accessions of a hyperaccumulating species., (© 2023. The Author(s).)

Background: Older men (aged ≥75 years) with high risk, non-metastatic prostate cancer (PCa) are increasingly treated with curative therapy (surgery or radiotherapy). However, it is unclear if curative therapy prolongs life and improves health-related quality of life (HRQoL) in this age group compared to conservative therapy, which has evolved considerably during the last decade., Study Design: The Scandinavian Prostate Cancer Group (SPCG) 19/Norwegian Get-Randomized Research Group-Prostate (GRand-P) is a randomised, two-armed, controlled, multicentre, phase III trial carried out at study centres in Norway, Denmark, Finland, and Sweden., Endpoints: The primary endpoints are overall survival and HRQoL (burden of disease scale, European Organisation for the Research and Treatment of Cancer [EORTC] Elderly Cancer patients). Secondary endpoints are PCa-specific survival, metastasis-free survival, role-functioning scale (EORTC quality of life questionnaire 30-item core), urinary irritative/obstructive scale (26-item Expanded Prostate Cancer Index Composite [EPIC-26]), bowel scale (EPIC-26), intervention-free survival, PCa morbidity, use of secondary and tertiary systemic therapies, mean quality-adjusted life-years (QALYs), and mean total healthcare costs., Patients and Methods: A total of 980 men (aged ≥75 years) with non-metastatic, high-risk PCa will initially be screened with Geriatric 8 (G8) health status screening tool and Mini-COG© brief cognitive test. Participants identified by G8 as 'fit' or 'frail' will be randomised (ratio 1:1) to either immediate curative therapy (radiotherapy or prostatectomy) or conservative therapy (endocrine therapy or observation). Participants who are unable or unwilling to participate in randomisation will be enrolled in a separate observation group. Randomised patients will be followed for 10 years., Trial Registration: Ethics approval has been granted in Norway (457593), Denmark (H-22051998), Finland (R23043) and Sweden (Dnr 2023-05296-01). The trial is registered on Clinicaltrials.org (NCT05448547)., (© 2024 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Deciphering the structural intricacies of catalysts is essential to advance their atomic-scale engineering. Solid catalysts are complex, with structural features spanning multiple length scales and involving dynamics, which possess challenges in understanding structure-performance relationships. However, advanced operando X-ray characterization techniques, including X-ray absorption spectroscopy (XAS), diffraction (XRD), and pair distribution function analysis (PDF) allow elucidation of structural features under working conditions, discovering transitions from supported nanocrystals to dispersed sites, from solid solutions to supported nanoparticles, or structural changes at the local level. In this mini-review, we discuss case studies exploring the structure of catalysts over different lengths and time scales under different applications, such as CO2 hydrogenation to methanol or the dry reforming of methane, using a combination of operando XAS, XRD and PDF., (Copyright 2024 Paula Abdala, Christoph Müller. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

Background: Infections with Herpes simplex virus (HSV)-1 or -2 usually present as mild chronic recurrent disease, however in rare cases can result in life-threatening conditions with a large spectrum of pathology. Monoclonal antibody therapy has great potential especially to treat infections with virus resistant to standard therapies. HDIT101, a humanized IgG targeting HSV-1/2 gB was previously investigated in phase 2 clinical trials. The aim of this study was to develop a next-generation therapy by combining different antiviral monoclonal antibodies., Methods: A lymph-node derived phage display library (LYNDAL) was screened against recombinant gB from Herpes simplex virus (HSV) -1 and HDIT102 scFv was selected for its binding characteristics using bio-layer interferometry. HDIT102 was further developed as fully human IgG and tested alone or in combination with HDIT101, a clinically tested humanized anti-HSV IgG, in vitro and in vivo. T-cell stimulating activities by antigen-presenting cells treated with IgG-HSV immune complexes were analyzed using primary human cells. To determine the epitopes, the cryo-EM structures of HDIT101 or HDIT102 Fab bound to HSV-1F as well as HSV-2G gB protein were solved at resolutions < 3.5 Å., Results: HDIT102 Fab showed strong binding to HSV-1F gB with Kd of 8.95 × 10 -11 M and to HSV-2G gB with Kd of 3.29 × 10 -11 M. Neutralization of cell-free virus and inhibition of cell-to-cell spread were comparable between HDIT101 and HDIT102. Both antibodies induced internalization of gB from the cell surface into acidic endosomes by binding distinct epitopes in domain I of gB and compete for binding. CryoEM analyses revealed the ability to form heterogenic immune complexes consisting of two HDIT102 and one HDIT101 Fab bound to one gB trimeric molecule. Both antibodies mediated antibody-dependent phagocytosis by antigen presenting cells which stimulated autologous T-cell activation. In vivo, the combination of HDIT101 and HDIT102 demonstrated synergistic effects on survival and clinical outcome in immunocompetent BALB/cOlaHsd mice., Conclusion: This biochemical and immunological study showcases the potential of an effective combination therapy with two monoclonal anti-gB IgGs for the treatment of HSV-1/2 induced disease conditions., (© 2024. The Author(s).)

In addition to patient care, physiotherapy is increasingly important in research at university hospitals. Genuine physiotherapy research plays a decisive role in this. This position statement describes the opportunities, benefits, framework conditions, challenges, and research priorities of genuine physiotherapy research at German university hospitals., Competing Interests: The authors declare that they have no competing interests, (Copyright © 2024 Klotz et al.)

A certified reference material of ricin (CRM-LS-1) was produced by the EuroBioTox consortium to standardise the analysis of this biotoxin. This study established the N -glycan structures and proportions including their loci and occupancy of ricin CRM-LS-1. The glycan profile was compared with ricin from different preparations and other cultivars and isoforms. A total of 15 different oligomannosidic or paucimannosidic structures were identified in CRM-LS-1. Paucimannose was mainly found within the A-chain and oligomannose constituted the major glycan type of the B-chain. Furthermore, the novel primary structure variants E138 and D138 and four different C-termini of the A-chain as well as two B-chain variants V250 and F250 were elucidated. While the glycan proportions and loci were similar among all variants in CRM-LS-1 and ricin isoforms D and E of all cultivars analysed, a different stoichiometry for isoforms D and E and the amino acid variants were found. This detailed physicochemical characterization of ricin regarding the glycan profile and amino acid sequence variations yields unprecedented insight into the molecular features of this protein toxin. The variable attributes discovered within different cultivars present signature motifs and may allow discrimination of the biotoxin's origin that are important in molecular forensic profiling. In conclusion, our data of in-depth CRM-LS-1 characterization combined with the analysis of other cultivars is representative for known ricin variants.

Objective: To evaluate incidence and predictors of early silent bypass occlusion following coronary bypass surgery using cardiac computed tomography angiography., Methods: A total of 439 consecutive patients with mean age of 66 ± 10 years comprising 17% ( n  = 75) females underwent isolated coronary bypass surgery followed by CT scan before discharge. Graft patency was evaluated in 1,319 anastomoses where 44% ( n  = 580) arterial and 56% ( n  = 739) vein graft anastomosis were performed. Cardiovascular risk factors, demographics, and intraoperative variables were analyzed. We conducted univariable and multivariable logistic regression analyses to analyze variables potentially associated with graft occlusion following CABG. Variables included gender, surgery duration, graft flow, pulsatility index, vein vs. artery graft, and recent MI., Results: Overall incidence of graft occlusion was 2.4% (31/1,319), and it was diagnosed in 6.6% (29/439) of patients. The difference in occlusion between arterial (2.1%) and vein (2.6%) grafts was not significant, p  = 0.68. The duration of intervention p  = 0.034, cross clamp time p  = 0.024 as well the number of distal anastomosis p  = 0.034 were significantly higher in occlusion group. The univariate and multivariate logistic regression indicated duration of surgery being predictive for bypass graft occlusion with OR = 1.18; 95% CI: 1.01-1.38; p  = 0.035., Conclusions: Early graft occlusion was associated with surgical factors. The number of distant anastamoses, along duration of surgical intervention were, significantly influenced the risk of EGO. Prolonged procedural time reflecting complex coronary pathology and time-consuming revascularization procedure was as well associated to the elevated risk of occlusion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Salikhanov, Koechlin, Gahl, Reuthebuch, Zellweger, Haaf, Bremerich, Pradella, Müller and Berdajs.)

Lack of nitrogen limits food production in poor countries while excessive nitrogen use in industrial countries has led to transgression of the planetary boundary. However, the potential of spatial redistribution of nitrogen input for food security when returning to the safe boundary has not been quantified in a robust manner. Using an emulator of a global gridded crop model ensemble, we found that redistribution of current nitrogen input to major cereals among countries can double production in the most food-insecure countries, while increasing global production of these crops by 12% with no notable regional loss or reducing the nitrogen input to the current production by one-third. Redistribution of the input within the boundary increased production by 6-8% compared to the current relative distribution, increasing production in the food-insecure countries by two-thirds. Our findings provide georeferenced guidelines for redistributing nitrogen use to enhance food security while safeguarding the planet., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Background: Despite continuous advances in post-resuscitation management, outcome after out-of-hospital cardiac arrest (OHCA) is limited. To improve the outcome, interdisciplinary Cardiac Arrest Centers (CACs) have been established in recent years, but survival remains low and treatment strategies vary considerably in clinical and geographical aspects. Here we analyzed a strategy of in-hospital post-resuscitation management while evaluating the outcome., Methods: A broad spectrum of pre- and in-hospital parameters of 545 resuscitated patients, admitted to the Cardiac Arrest Center of the University Hospital of Marburg (MCAC) between 01/2018 and 12/2022 were retrospectively analyzed. Inclusion criteria were ≥ 18 years, resuscitation by emergency medical services, and non-traumatic cause of OHCA., Results: In the overall patient cohort, the survival rate to hospital discharge was 39.8% (n = 217/545), which is 50.7% higher than in the EuReCa-TWO registry. 77.2% of the survivors had CPC status 1 or 2 (favorable neurological outcome) before and after therapy. A standardized 'therapy bundle' for in-hospital post-resuscitation management was applied to 445 patients who survived the initial treatment in the emergency department. In addition to basic care (standardized antimicrobial therapy, adequate anticoagulation, targeted sedation, early enteral and parenteral nutrition), it includes early whole-body CT (n = 391; 87.9%), invasive coronary diagnostics (n = 322; 72.4%), targeted temperature management (n = 293; 65.8%) and if indicated, mechanical circulatory support (n = 145; 32.6%) and appropriate neurological diagnostics., Conclusions: Early goal-directed post-resuscitation management in a well-established and highly frequented CAC leads to significantly higher survival rates. However, our results underline the need for a broader standardization in post-resuscitation management to ultimately improve the outcome., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: According to social-ecological models, the built and natural environment has the potential to facilitate or hinder physical activity (PA). While this potential is well researched in urban areas, a current systematic review of how the built and natural environment is related to PA in rural areas is lacking., Methods: We searched five databases and included studies for adults (18-65 years) living in rural areas. We included quantitative studies investigating the association between any self-reported or objectively measured characteristic of the built or natural environment and any type of self-reported or objectively measured PA, and qualitative studies that reported on features of the built or natural environment perceived as barriers to or facilitators of PA by the participants. Screening for eligibility and quality assessment (using the Standard Quality Assessment Criteria for Evaluating Primary Research Papers from a Variety of Fields) were done in duplicate. We used a narrative approach to synthesize the results., Results: Of 2432 non-duplicate records, 51 quantitative and 19 qualitative studies were included. Convincing positive relationships were found between the availability and accessibility of places for exercise and recreation and leisure-time PA as well as between the overall environment and leisure-time PA. Possible positive associations were found between the overall environment and total and transport-related PA, between greenness/natural environment and total PA, between cycling infrastructure and aesthetics and MVPA, and between pedestrian infrastructure and total walking. A possible negative relationship was found between safety and security and total walking. Qualitative studies complemented several environmental facilitators (facilities for exercise and recreation, sidewalks or streets with low traffic, attractive natural environment) and barriers (lack of facilities and destinations, lack of sidewalks, speeding traffic and high traffic volumes, lack of street lighting)., Conclusions: Research investigating the relationship between the built and natural environment and PA behaviors of adults living in rural areas is still limited and there is a need for more high-quality and longitudinal studies. However, our most positive findings indicate that investing in places for exercise and recreation, a safe infrastructure for active transport, and nature-based activities are possible strategies that should be considered to address low levels of PA in rural adults., Trial Registration: PROSPERO: CRD42021283508., (© 2024. The Author(s).)

Background: Patients with congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD) and dementia are underrepresented in specialist palliative home care (SPHC). However, the complexity of their conditions requires collaboration between general practitioners (GPs) and SPHC teams and timely integration into SPHC to effectively meet their needs., Objective: To facilitate joint palliative care planning and the timely transfer of patients with advanced chronic non-malignant conditions to SPHC., Methods: A two-arm, unblinded, cluster-randomised controlled trial. 49 GP practices in northern Germany were randomised using web-based block randomisation. We included patients with advanced CHF, COPD and/or dementia. The KOPAL intervention consisted of a SPHC nurse-patient consultation followed by an interprofessional telephone case conference between SPHC team and GP. The primary outcome was the number of hospital admissions 48 weeks after baseline. Secondary analyses examined the effects on health-related quality of life and self-rated health status, as measured by the EuroQol 5D scale., Results: A total of 172 patients were included in the analyses. 80.4% of GP practices had worked with SHPC before, most of them exclusively for cancer patients. At baseline, patients reported a mean EQ-VAS of 48.4, a mean quality of life index (EQ-5D-5L) of 0.63 and an average of 0.80 hospital admissions in the previous year. The intervention did not significantly reduce hospital admissions (incidence rate ratio = 0.79, 95%CI: [0.49, 1.26], P = 0.31) or the number of days spent in hospital (incidence rate ratio = 0.65, 95%CI: [0.28, 1.49], P = 0.29). There was also no significant effect on quality of life (∆ = -0.02, 95%CI: [-0.09, 0.05], P = 0.53) or self-rated health (∆ = -2.48, 95%CI: [-9.95, 4.99], P = 0.51)., Conclusions: The study did not show the hypothesised effect on hospitalisations and health-related quality of life. Future research should focus on refining this approach, with particular emphasis on optimising the timing of case conferences and implementing discussed changes to treatment plans, to improve collaboration between GPs and SPHC teams., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: There has been no previous thorough toxicological examination of a cohort of patients with resuscitated sudden cardiac arrest. We aimed to determine the qualitative and quantitative drug composition in a resuscitated sudden cardiac arrest population, using forensic toxicology, with focus on prescribed, non-prescribed, and commonly abused drugs., Methods: Individuals aged 18-90 years with resuscitated sudden cardiac arrest of presumed cardiac causes were prospectively included from a single tertiary center. Data from the sudden cardiac arrest hospitalization was collected from medical reports. Drugs used during resuscitation or before the blood sampling were identified and excluded in each patient. Mass spectrometry-based toxicology was performed to determine the absence or presence of most drugs and to quantify the findings., Results: Among 186 consecutively enrolled resuscitated sudden cardiac arrest patients (median age 62 years, 83% male), 90% had a shockable rhythm, and were primarily caused by ischemic heart disease (66%). In total, 90 different drugs (excluding metabolites) were identified, and 82% of patients had at least one drug detected (median of 2 detected drugs (IQR:1-4)) (polypharmacy). Commonly abused drugs were present in 16%, and QT-prolonging drugs were present in 12%. Polypharmacy (≥5drugs) were found in 19% of patients. Importantly, none had potentially lethal concentrations of any drugs., Conclusion: In resuscitated sudden cardiac arrest patients with cardiac arrest of presumed cardiac cause, routine toxicological screening provides limited extra information. However, the role of polypharmacy in sudden cardiac arrest requires further investigation. No occult overdose-related cardiac arrests were identified., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: NKS and PB was supported by research grants from the European Union’s Horizon 2020 research and innovation programme to JTH under acronym ESCAPE-NET (733381). BGW was supported by research grants from the Danish Heart Foundation and University Hospital Copenhagen, Rigshospitalets Science board. CPM was funded by a personal grant from the Research Foundation at Rigshospitalet. CH was founded by the Lundbeck Foundation, Novo Nordisk Foundation and The Danish Heart Foundation. CG was supported by a research grant from the Danish Cardiovascular Academy, which is funded by the Novo Nordisk Foundation and The Danish Heart Foundation, Grant ID number: CPD5Y-2022003-HF)’., (Copyright © 2024 Elsevier B.V. All rights reserved.)