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Introduction: Clear cell Renal Cell Carcinoma (ccRCC) has a poor prognosis once metastatic. However, certain metastatic sites have been reported to have a different impact on the patient prognosis. For example, patients with pancreatic metastases have a much more favorable prognosis than those with metastases to other organs. The biological basis for this observation remains poorly understood. The aim of this study was to characterize the immune landscape of pancreatic metastases and the corresponding primary tumors in order to identify possible immunological features that correlate with disease biology., Patients and Methods: A detailed assessment of immune cell populations was performed using a total of 1,700 microscopic images from ccRCCs from 11 patients, their corresponding pancreatic metastases and ccRCCs from 10 patients without pancreatic metastases. Tumor specimens were stained for CD45, CD8, CD163 and FOXP3 and the densities of the respective immune cells were assessed semiquantitatively in the intratumoral and extratumoral compartment. Multispectral imaging was performed in selected tumors., Results: We found that pancreatic metastases show the lowest intratumoral infiltration with CD8 + cytotoxic T lymphocytes of all tumor specimens analyzed. The frequency of CD8 + lymphocytes was on 1.9 fold lower in pancreatic metastases (median density 8.3 cells per field of view [FOV] = 1.23 mm 2 ) when compared to the corresponding primary tumor (15.6 cells per FOV, P = 0.0002) and more than 3-fold lower when compared to ccRCCs without pancreatic metastases (27.2 cells per FOV, P = 0.0012). There was also a significantly reduced intratumoral infiltration with immunosuppressive FOXP3 + lymphocytes in pancreatic metastases (2.6 cells per FOV, P = 0.009) and corresponding primary tumors (2 cells per FOV, P = 0.028) when compared to ccRCCs without pancreatic metastases (5.6 cells per FOV)., Conclusions: In this proof-of-concept study, we show that pancreatic metastases of ccRCC present with unique immunological features including a low intratumoral density of CD8 + and FOXP3 + lymphocytes. The low counts of CD8 + and FOXP3 + lymphocytes may reflect less aggressive features of ccRCC with pancreatic metastasis that may result in a more favorable patient prognosis., 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.)

Protein-protein interactions (PPIs) regulate signalling pathways and cell phenotypes, and the visualization of spatially resolved dynamics of PPIs would thus shed light on the activation and crosstalk of signalling networks. Here we report a method that leverages a sequential proximity ligation assay for the multiplexed profiling of PPIs with up to 47 proteins involved in multisignalling crosstalk pathways. We applied the method, followed by conventional immunofluorescence, to cell cultures and tissues of non-small-cell lung cancers with a mutated epidermal growth-factor receptor to determine the co-localization of PPIs in subcellular volumes and to reconstruct changes in the subcellular distributions of PPIs in response to perturbations by the tyrosine kinase inhibitor osimertinib. We also show that a graph convolutional network encoding spatially resolved PPIs can accurately predict the cell-treatment status of single cells. Multiplexed proximity ligation assays aided by graph-based deep learning can provide insights into the subcellular organization of PPIs towards the design of drugs for targeting the protein interactome., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Predictors of symptom improvement are an essential starting point for tailoring psychological treatments to each individual and, in turn, increasing treatment efficacy overall. However, such research regarding refugees/asylum seekers from Arabic-/Farsi-speaking countries is lacking. The current study aimed to characterize predictors for symptom improvement in the Mental Health in Refugees and Asylum Seekers (MEHIRA) study, one of the most extensive multicentered controlled trials on a nationwide stepped and collaborative care model compared to routine German mental health care., Methods: Variables characterizing symptom change were chosen using backward elimination and inserted into logistic regression models for two depression endpoints, namely the Patient Health Questionnaire-9 (PHQ-9) and the Montgomery Asberg Depression Rating Scale (MADRS)., Results: Six variables were found to be at least marginally significantly associated with symptom decrease in both outcomes: baseline depressive symptom load, comorbid post-traumatic stress disorder, identifying as a refugee, years of schooling, physical health, and post-migration social status difference. Additionally, psychological health and resilience were marginally significant for one of the models., Limitations: Some predictor constructs - such as social support - were not adequately measured to replicate previous findings. Additionally, the study was underpowered for symptom change prediction of individual treatments beyond the group intervention., Conclusions: These outcomes indicate that trauma-related elements as well as content on refugee identity and post-migration social status changes should be included in depression interventions for refugees. Further, recommendations for future outcome prediction studies are made., Competing Interests: Declaration of competing interest Dr. Banaschewski served in an advisory or consultancy role for eye level, Infectopharm, Medice, Neurim Pharmaceuticals, Oberberg GmbH and Takeda. He received conference support or speaker's fee by Janssen-Cilag, Medice and Takeda. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. Alkomiet Hasan is editor of the German (DGPPN) schizophrenia treatment guidelines, first author of the WFSBP schizophrenia treatment guidelines; on advisory boards of and speaker fees from AbbVie (speaker fees only), Advanz (speaker fees only), Janssen-Cilag, Lundbeck, Recordati, Rovi, and Otsuka. Paul Plener was involved in clinical trials of Lundbeck and Servier. He received a speaker's honorarium from Shire and Infectopharm. Frank Padberg is a member of the European Scientific Advisory Board of Brainsway Inc., Jerusalem, Israel, and has received speaker's honoraria from Mag&More GmbH and the neuroCare Group. His lab has received support with equipment from neuroConn GmbH, Ilmenau, Germany, and Mag&More GmbH and Brainsway Inc., Jerusalem, Israel. Malek Bajbouj is member of advisory boards for Bayer and GH Research. The other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Chatbots are computer programs designed to engage in natural language conversations in an easy and understandable way. Their use has been accelerated recently with the advent of large language models. However, their application in medicine and healthcare has been limited due to concerns over data privacy, the risk of providing medical diagnoses, and ensuring regulatory and legal compliance. Medicine and healthcare could benefit from chatbots if their scope is carefully defined and if they are used appropriately and monitored long-term. The confIAnce chatbot, developed at the Geneva University Hospitals and the University of Geneva, is an informational tool aimed at providing simplified information to the general public about primary care and chronic diseases. In this paper, we describe the certification and regulatory aspects applicable to chatbots in healthcare, particularly in primary care medicine. We use the confIAnce chatbot as a case study to explore the definition and classification of a medical device and its application to chatbots, considering the applicable Swiss regulations and the European Union AI Act. Chatbots can be classified anywhere from non-medical devices (informational tools that do not handle patient data or provide recommendations for treatment or diagnosis) to Class III medical devices (high-risk tools capable of predicting potentially fatal events and enabling a pre-emptive medical intervention). Key considerations in the definition and certification process include defining the chatbot's scope, ensuring compliance with regulations, maintaining security and safety, and continuously evaluating performance, risks, and utility. A lexicon of relevant terms related to artificial intelligence in healthcare, medical devices, and regulatory frameworks is also presented in this paper. Chatbots hold potential for both patients and healthcare professionals, provided that their scope of practice is clearly defined, and that they comply with regulatory requirements. This review aims to provide transparency by outlining the steps required for certification and regulatory compliance, making it valuable for healthcare professionals, scientists, developers, and patients.

Background: Despite scarce data, invasive mechanical ventilation (MV) is widely suggested as first-line ventilatory support in cardiogenic shock (CS) patients. We assessed the real-life use of different ventilation strategies in CS and their influence on short and mid-term prognosis., Methods: FRENSHOCK was a prospective registry including 772 CS patients from 49 centers in France. Patients were categorized into three groups according to the ventilatory supports during hospitalization: no mechanical ventilation group (NV), non-invasive ventilation alone group (NIV), and invasive mechanical ventilation group (MV). We compared clinical characteristics, management, and occurrence of death and major adverse event (MAE) (death, heart transplantation or ventricular assist device) at 30 days and 1 year between the three groups., Results: Seven hundred sixty-eight patients were included in this analysis. Mean age was 66 years and 71% were men. Among them, 359 did not receive any ventilatory support (46.7%), 118 only NIV (15.4%), and 291 MV (37.9%). MV patients presented more severe CS with more skin mottling, higher lactate levels, and higher use of vasoactive drugs and mechanical circulatory support. MV was associated with higher mortality and MAE at 30 days (HR 1.41 [1.05-1.90] and 1.52 [1.16-1.99] vs NV). No difference in mortality (HR 0.79 [0.49-1.26]) or MAE (HR 0.83 [0.54-1.27]) was found between NIV patients and NV patients. Similar results were found at 1-year follow-up., Conclusions: Our study suggests that using NIV is safe in selected patients with less profound CS and no other MV indication. NCT02703038., (© 2024. The Author(s).)

Purpose: Current bulk molecular assays fail to capture spatial signaling activities in cancers, limiting our understanding of drug resistance mechanisms. We developed a graph-based super-resolution protein-protein interaction (GSR-PPI) technique to spatially resolve single-cell signaling networks and evaluate whether higher resolution microscopy enhances the biological study of PPIs using deep learning classification models., Methods: Single-cell spatial proximity ligation assays (PLA, ≤ 9 PPI pairs) were conducted on EGFR mutant (EGFRm) PC9 and HCC827 cells (>10,000 cells) treated with 100 nM Osimertinib. Multiplexed PPI images were obtained using wide-field and super-resolution microscopy (Zeiss Airyscan, SRRF). Graph-based deep learning models analyzed subcellular protein interactions to classify drug treatment states and test GSR-PPI on clinical tissue samples. GSR-PPI triangulated PPI nodes into 3D relationships, predicting drug treatment labels. Biological discriminative ability (BDA) was evaluated using accuracy, AUC, and F1 scores. The method was also applied to 3D spatial proteomic molecular pixelation (PixelGen) data from T cells., Results: GSR-PPI outperformed baseline models in predicting drug responses from multiplexed PPI imaging in EGFRm cells. Super-resolution data significantly improved accuracy over localized wide-field imaging. GSR-PPI classified drug treatment states in cancer cells and human lung tissues, with performance improving as imaging resolution increased. It differentiated single and combination drug therapies in HCC827 cells and human tissues. Additionally, GSR-PPI accurately distinguished T-cell stimulation states, identifying key nodes such as CD44, CD45, and CD54., Conclusion: The GSR-PPI framework provides valuable insights into spatial protein interactions and drug responses, enhancing the study of signaling biology and drug resistance., Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-024-00822-1., Competing Interests: Conflict of interestCoskun, Cai, and Hu declare a patent application related to the spatial signaling interactomics assay (US Provisional 63/399,427 and US Application No 18/452,178). Nicholas Zhang, Mingshuang Wang, Frank Schneider, and Shi-Yong Sun declare no competing interests., (© The Author(s), under exclusive licence to Biomedical Engineering Society 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The quantum-mechanical nuclear-shell structure determines the stability and limits of the existence of the heaviest nuclides with large proton numbers Z ≳ 100 (refs. 1-3 ). Shell effects also affect the sizes and shapes of atomic nuclei, as shown by laser spectroscopy studies in lighter nuclides 4 . However, experimental information on the charge radii and the nuclear moments of the heavy actinide elements, which link the heaviest naturally abundant nuclides with artificially produced superheavy elements, is sparse 5 . Here we present laser spectroscopy measurements along the fermium (Z = 100) isotopic chain and an extension of data in the nobelium isotopic chain (Z = 102) across a key region. Multiple production schemes and different advanced techniques were applied to determine the isotope shifts in atomic transitions, from which changes in the nuclear mean-square charge radii were extracted. A range of nuclear models based on energy density functionals reproduce well the observed smooth evolution of the nuclear size. Both the remarkable consistency of model prediction and the similarity of predictions for different isotopes suggest a transition to a regime in which shell effects have a diminished effect on the size compared with lighter nuclei., (© 2024. The Author(s).)

Background: There is a research gap in the survey of injuries and illnesses in the sport of luge., Objective: To analyse the type, frequency and burden of injuries and illnesses that occurred over a preparation period and a competition period in elite luge athletes., Methods: In total 40 elite luge athletes, who were all part of a national team and competed internationally, self-reported acute injuries, overuse injuries and illnesses weekly using the Oslo Sports Trauma Research Centre Questionnaire on Health Problems., Results: The most frequently stated health problems were illnesses with 41.9% (n=75), followed by acute injuries at 31.9% (n=57). Overuse injuries accounted for 24.0% (n=43). Illnesses represented the greatest burden with a median severity score of 60.0 (IQR: 23.63), followed by acute injuries with 42.0 (IQR: 26.83) and overuse injuries with 35.0 (IQR: 23.95). In the case of acute injuries, the anatomical regions most affected were the hand (n=8, 14.0 %), foot (n=8, 14.0 %), head (n=7, 12.3 %) and neck (n=6, 10.5 %). In the case of overuse injuries, the shoulder (n=9, 20.9 %) and lumbar spine (n=7, 16.3 %) were most frequently reported. Strains (n=15, 26.3 %) and contusions (n=14, 24.6 %) were the predominant types of acute injuries. Four concussions were recorded, with none of the athletes taking a break from normal training of more than 3 days. This stands in contrast to the current recommendations for the return to sport after concussion., Conclusion: The results of this study represent the current incidence rates and health burden of acute and chronic injuries in this constantly evolving sport. 95% of all athletes reported at least one health problem during the observation period. These findings support the need for specific prevention programmes. The establishment of a concussion protocol should be considered., Competing Interests: None declared., (Copyright © 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.)

Context.—: Biomarker reporting has increasingly become a key component of pathology reporting, providing diagnostic, prognostic, and actionable therapeutic data for patient care., Objective.—: To expand and improve the College of American Pathologists (CAP) biomarker protocols., Design.—: We surveyed CAP members to better understand the limitations they experienced when reporting cancer biomarker results. A Biomarker Workgroup reviewed the survey results and developed a strategy to improve and standardize biomarker reporting. Drafts of new and revised biomarker protocols were reviewed in both print and electronic template formats during interactive webinars presented to the CAP House of Delegates. Feedback was collected, and appropriate revisions were made to finalize the protocols., Results.—: The first phase of the CAP Biomarker Workgroup saw the development of (1) a new stand-alone general Immunohistochemistry Biomarker Protocol that includes reporting for ER (estrogen receptor), PR (progesterone receptor), Ki-67, HER2 (human epidermal growth factor receptor 2), PD-L1 (programmed death ligand-1), and mismatch repair; (2) a new Head and Neck Biomarker Protocol that updates the prior 2017 paper-only version into an electronic template, adding new diagnostic and theranostic markers; (3) a major revision to the Lung Biomarker Protocol to streamline it and add in pan-cancer markers; and (4) a revision to the Colon and Rectum Biomarker Protocol to add HER2 reporting., Conclusions.—: We have taken a multipronged approach to improving biomarker reporting in the CAP cancer protocols. We continue to review current biomarker reporting protocols to reduce and eliminate unnecessary methodologic details and update with new markers as needed. The biomarker templates will serve as standardized modular units that can be inserted into cancer-reporting protocols., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

International literature is lacking quantified information about the impact of raising demands for attractive appearances and the private standards on food loss and associated effects on the economy, the environment and social issues. Given the global scale and significance to food consumption and health, fresh apples were selected for researching the issues. By focusing on China, the major production region of fresh apple in the world where the effects of aesthetic preference and shape abnormality are substantial, the present study aims to gain insights into the on-farm grading processes and different marketing channels for fresh apples in China. It was discovered that 35% of the volume in China's major production areas of fresh apples were graded by aesthetic characteristics such as ripeness, colour, fragrance, bruising, intactness and appealing appearance. About 17.1% of production on average were considered as food losses mainly caused by such grading schemes. Favouring 'perfect' appearance; however, the grading did not yield economic benefits for smallholders. Lastly, direct procurement by supermarkets had a depressive effect on the price of fresh apples at the farm gate. The study has a unique value for global debates and actions against food loss and waste as it quantifies on-farm post-harvest losses of fresh apples by different agri-food chain organizations in China with respect to mass and economic value., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Artificial neural networks (ANNs) have proven to be a useful tool for complex questions that involve large amounts of data. Our use case of predicting soil maps with ANNs is in high demand by government agencies, construction companies, or farmers, given cost and time intensive field work. However, there are two main challenges when applying ANNs. In their most common form, deep learning algorithms do not provide interpretable predictive uncertainty. This means that properties of an ANN such as the certainty and plausibility of the predicted variables, rely on the interpretation by experts rather than being quantified by evaluation metrics validating the ANNs. Further, these algorithms have shown a high confidence in their predictions in areas geographically distant from the training area or areas sparsely covered by training data. To tackle these challenges, we use the Bayesian deep learning approach "last-layer Laplace approximation", which is specifically designed to quantify uncertainty into deep networks, in our explorative study on soil classification. It corrects the overconfident areas without reducing the accuracy of the predictions, giving us a more realistic uncertainty expression of the model's prediction. In our study area in southern Germany, we subdivide the soils into soil regions and as a test case we explicitly exclude two soil regions in the training area but include these regions in the prediction. Our results emphasize the need for uncertainty measurement to obtain more reliable and interpretable results of ANNs, especially for regions far away from the training area. Moreover, the knowledge gained from this research addresses the problem of overconfidence of ANNs and provides valuable information on the predictability of soil types and the identification of knowledge gaps. By analyzing regions where the model has limited data support and, consequently, high uncertainty, stakeholders can recognize the areas that require more data collection efforts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Object-based attention operates both in perception and visual working memory. While the efficient perception of auditory stimuli also requires the formation of auditory objects, little is known about their role in auditory working memory (AWM). To investigate whether attention to one object feature in AWM leads to the involuntary maintenance of another, task-irrelevant feature, we conducted four experiments. Stimuli were abstract sounds that differed on the dimensions frequency and location, only one of which was task-relevant in each experiment. The first two experiments required a match-nonmatch decision about a probe sound whose irrelevant feature value could either be identical to or differ from the memorized stimulus. Matches on the relevant dimension were detected more accurately when the irrelevant feature matched as well, whereas for nonmatches on the relevant dimension, performance was better for irrelevant feature nonmatches. Signal-detection analysis showed that changes of irrelevant frequency reduced the sensitivity for sound location. Two further experiments used continuous report tasks. When location was the target feature, changes of irrelevant sound frequency had an impact on both recall error and adjustment time. Irrelevant location changes affected adjustment time only. In summary, object-based attention led to a concurrent maintenance of task-irrelevant sound features in AWM., (© 2024. The Author(s).)

Background: Black women are at an increased risk of developing uterine leiomyomas and experiencing worse disease prognosis than White women. Epidemiologic and molecular factors have been identified as underlying these disparities, but there remains a paucity of deep, multiomic analysis investigating molecular differences in uterine leiomyomas from Black and White patients., Objective: To identify molecular alterations within uterine leiomyoma tissues correlating with patient race by multiomic analyses of uterine leiomyomas collected from cohorts of Black and White women., Study Design: We performed multiomic analysis of uterine leiomyomas from Black (42) and White (47) women undergoing hysterectomy for symptomatic uterine leiomyomata. In addition, our analysis included the application of orthogonal methods to evaluate fibroid biomechanical properties, such as second harmonic generation microscopy, uniaxial compression testing, and shear-wave ultrasonography analyses., Results: We found a greater proportion of MED12 mutant uterine leiomyomas from Black women (>35% increase; Mann-Whitney U, P<.001). MED12 mutant tumors exhibited an elevated abundance of extracellular matrix proteins, including several collagen isoforms, involved in the regulation of the core matrisome. Histologic analysis of tissue fibrosis using trichrome staining and secondary harmonic generation microscopy confirmed that MED12 mutant tumors are more fibrotic than MED12 wild-type tumors. Using shear-wave ultrasonography in a prospectively collected cohort, Black patients had fibroids that were firmer than White patients, even when similar in size. In addition, these analyses uncovered ancestry-linked expression quantitative trait loci with altered allele frequencies in African and European populations correlating with differential abundance of several proteins in uterine leiomyomas independently of MED12 mutation status, including tetratricopeptide repeat protein 38., Conclusion: Our study shows that Black women have a higher prevalence of uterine leiomyomas harboring mutations in MED12 and that this mutational status correlates with increased tissue fibrosis compared with wild-type uterine leiomyomas. Our study provides insights into molecular alterations correlating with racial disparities in uterine leiomyomas and improves our understanding of the molecular etiology underlying uterine leiomyoma development within these populations., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Reports on the effects of changing the United States Medical Licensing Exam (USMLE) Step 1 examination scoring to pass/fail are evolving in the medical literature. This Council of Academic Family Medicine Educational Research Alliance family medicine clerkship directors' study seeks to describe family medicine clerkship directors' perceptions on the impact of incorporation of Step 1 pass/fail score reporting on students' family medicine clerkship performance., Methods: Ninety-six clerkship directors responded (56.8% response rate). After exclusion of Canadian schools, we analyzed 88 clerkship directors' responses from US schools. We used descriptive statistics for demographics and responses to survey questions. We used ꭓ2 analysis to determine statistically significant associations between survey items., Results: Clerkship directors did not observe changes in students' overall clinical performance after Step 1 pass/fail scoring (60.8%). Fifty percent of clerkship directors reported changes in Step 1 timing recommendations in the past 3 years. Reasons included curriculum redesign (30.5%), COVID (4.5%), change in Step 1 to pass/fail (11.0%), and other reasons (3.7%). Forty-five percent of these clerkship directors did not observe a change in students' clinical medical knowledge after Step 1 went to pass/fail. Eighty-four percent of these clerkship directors did not compare student performance on clerkship standardized exams before and after Step 1 score changes. We found no significant relationship between Step 1 timing and student performance., Conclusions: This study represents an early description of family medicine clerkship directors' perceived observations of the impact of Step 1 scoring changes on student performance. Continued investigation of the effects of USMLE Step 1 pass/fail scoring should occur.

Prostate cancer is characterized by a high degree of intratumoral heterogeneity. However, little is known about the spatial distribution of cancer cells with respect to specific functional characteristics and the formation of spatial niches. Here, we used digital spatial profiling (DSP) to investigate differences in protein expression in the tumor center versus the tumor periphery. Thirty-seven regions of interest were analyzed for the expression of 47 proteins, which included components of the PI3K-AKT, MAPK, and cell death signaling pathways as well as immune cell markers. A total of 1739 data points were collected from five patients. DSP identified the BCL-2 associated agonist of cell death (BAD) protein as the most significantly upregulated protein in the tumor center. BAD upregulation was confirmed by conventional immunohistochemistry, which furthermore showed a phosphorylation of BAD at serine 112 indicating its inactivation. Knockdown of BAD in prostate cancer cells in vitro led to decreased cell viability and colony growth. Clinically, high BAD expression was associated with a shorter time to biochemical recurrence in 158 mostly high-risk prostate cancer patients. Collectively, our results suggest that the tumor center is a topological niche with high BAD expression that may drive prostate cancer progression., (© 2024. The Author(s).)

Measuring forces within living cells remains a technical challenge. In this Tutorial, we cover the development of hydrophobic mechanosensing fluorescent probes called Flippers, whose fluorescence lifetime depends on lipid packing. Flipper probes can therefore be used as reporters for membrane tension via the measurement of changes in their fluorescence lifetime. We describe the technical optimization of the probe for imaging and provide working examples for their characterizations in a variety of biological and in vitro systems. We further provide a guideline to measure biophysical parameters of cellular membranes by fluorescence lifetime imaging microscopy using Flipper probes, providing evidence that flippers can report long range forces in cells, tissues and organs., (© 2024. Springer Nature Limited.)

Background: Spatial biology is an emerging concept to interrogate tumor heterogeneity. The NanoString GeoMx® Digital Spatial Profiling (DSP) platform has become increasingly available. It combines high-plex analysis of protein or messenger RNA expression using barcoded antibodies or oligonucleotide probes with investigator-driven selection of regions of interest. Cell populations, e.g. immune cells, can be selectively analyzed via segmentation. A key advantage is the use of archived formalin-fixed, paraffin-embedded tissue, however, begging the question whether and to what extent tissue fixation and storage time affect the results., Materials and Methods: Antibody binding density (ABD), i.e. the number of barcodes/μm 2 , is a key quality control measure for DSP spatial proteomics. To assess whether regional differences in tissue fixation have an influence on ABD, we compared 652 regions of interest selected from tumor center and periphery of 49 prostate cancer and 25 renal cell carcinoma (RCC) specimens. Moreover, the effect of tissue storage time on ABD was examined. Finally, we tested whether regional differences have an influence on ABD of segmented CD45+ or CD8+ cells., Results: No significant differences in ABD between tumor center and periphery were found in prostate cancer or RCC. However, ABD was significantly higher in recent specimens (≤5 years) when compared with those that were older (>5 years; P  = 0.027). There was a trend towards higher ABD in the tumor periphery of RCC specimens after segmentation for immune cells, albeit without reaching statistical significance., Conclusions: The NanoString GeoMx® DSP platform delivers robust data to interrogate tumor heterogeneity, but tissue storage time should be considered when interpreting the results., (© 2024 The Author(s).)

Cells crucially rely on the interactions of biomolecules at their plasma membrane to maintain homeostasis. Yet, a methodology to systematically quantify biomolecular organisation, measuring diffusion dynamics and oligomerisation, represents an unmet need. Here, we introduce the brightness-transit statistics (BTS) method based on fluorescence fluctuation spectroscopy and combine information from brightness and transit times to elucidate biomolecular diffusion and oligomerisation in both cell-free in vitro and in vitro systems incorporating living cells. We validate our approach in silico with computer simulations and experimentally using oligomerisation of EGFP tethered to supported lipid bilayers. We apply our pipeline to study the oligomerisation of CD40 ectodomain in vitro and endogenous CD40 on primary B cells. While we find a potential for CD40 to oligomerize in a concentration or ligand depended manner, we do not observe mobile oligomers on B cells. The BTS method combines sensitive analysis, quantification, and intuitive visualisation of dynamic biomolecular organisation., (© 2024. The Author(s).)

Engagement of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) can interfere with the CD28 signaling requisite for T-cell activation. While immune checkpoint inhibitors (ICIs) can relieve this suppression, they are unable to drive CD28 costimulation that may mechanistically contribute to ICI resistance. Thus, CD28 costimulation in the context of checkpoint inhibition may activate immunosuppressed T-cells in the tumor microenvironment. Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain (vIgD) designed to mediate PD-L1-dependent CD28 costimulation while inhibiting the PD-L1 and CTLA-4 checkpoints. PD-L1-restriction of davoceticept's CD28 costimulatory activity may minimize systemic T-cell activation and avoid untoward systemic toxicities. At the same time, preclinical studies have suggested that treatment with davoceticept during PD-1 inhibition may enhance antitumor activity by upregulating PD-L1, potentially synergizing with davoceticept's PD-L1-dependent costimulatory mechanism. This report details two cases of fatal cardiac events following treatment with davoceticept in combination with pembrolizumab (anti-PD-1) in the phase 1 study, NEON-2. Both events occurred in females in their 60s; one with choroidal melanoma and prior immunotherapy, the other with ICI-naïve microsatellite stable colorectal cancer. The clinical courses were fulminant with symptom onset at 2 weeks, followed by rapid decline. Cardiac autopsy from one patient confirmed immune-related myocarditis, and immunosequencing revealed expansion of a single T-cell clone that was not present in the pretreatment tumor. These cases highlight the importance of understanding risk factors that may contribute to immune-related myocarditis and other severe immune-related adverse events when CD28 agonism is targeted in the context of checkpoint inhibition.NEON-2 (NCT04920383)., Competing Interests: Competing interests: LC: Consultant: Janssen, AstraZeneca, Pliant Therapeutics, CDR-Life, Actuate TherapeuticsSRC: Research Support (institutional): Alpine Immune SciencesKL: Nothing to disclose. FS: Grants or Contracts: NIH P01 (Deciphering LKB1-associated immunotherapy resistance in lung adenocarcinoma). NL: Support for the present manuscript (institutional): Alpine Immune Sciences; Consulting Fees: SK Life Sciences; Research Funding (institutional): Alexo Therapeutics, Ascentage Pharma, BeiGene, Constellation Pharmaceuticals, Forty Seven, Loxo, Macrogenics, Merck, Pfizer, Regeneron, Apexian Pharmaceuticals, Coordination Therapeutics, Symphogen, CytomX Therapeutics, InhibRx, Incyte, Jounce Therapeutics, Livzon, Northern Biologics, Tesaro, Innovent Biologics, LAM Therapeutics, Ikena, Celgene, Shattuck Labs, Alpine Immune Sciences, Genmab, Odonate, Mersana, Seagen, Alpine Biosciences, Astellas Pharma, Celgene, Helsinn, Therapeutics, Ikena Oncology, Lilly, Sapience Therapeutics, Epizyme, Gilead, Glaxo Smith Kline, Tizona, Servier, Alkermes, KSQ, Repare Therapeutics, Biosplice/Samumed, Sapience Therapeutics, SK Life Sciences, Janssen, Arcus, Artios, BioNTech SE, Alkermes/Mural OncologyAE: Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune Sciences; Support for attending meetings: Alpine Immune Sciences; Patents planned, issued or pending: Tempest Therapeutics, University of CaliforniaHL: Former employee of Alpine Immune Sciences; Holds stock or stock options in Alpine Immune SciencesJS: Employee of Adaptive Biotechnologies; Holds stock in Adaptive Biotechnologies. HT: Support for present manuscript: Biostatistician supporting work on the manuscript; Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune SciencesMJC: Employee of Merck Sharp & Dohme, a subsidiary of Merck & Co., Rahway, New Jersey, USA; Owns stock in Merck & Co. SLP: Employee of Alpine Immune Sciences; Holds stock or stock options in Alpine Immune Sciences. AN: Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune SciencesDD: Support for present manuscript: Alpine Immune Sciences; Grants/Research Support (institutional): Arcus, CellSight Technologies, Immunocore, Merck, Regeneron Pharmaceuticals, Tesaro/GSK. Consulting Fees: ACM Bio, Ascendis Pharma; Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Merck, Medical Learning Group (MLG), Xilio Therapeutics. Payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events: Castle Biosciences. Patents planned, issued or pending: US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, December 11, 2020 US Patent 63/208,719, “Compositions and Methods For Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021., (© 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.)

Aim: The use of vitamin K antagonists (VKAs) may increase the risk of peripheral arterial disease (PAD) because vitamin K is a strong inhibitor of medial arterial calcification. Type 2 diabetes (T2D) exposes patients to an increased risk of PAD. We examined how the use of VKAs modulates the risk of incident PAD in people with T2D., Materials and Methods: SURDIAGENE is a French cohort including 1468 patients with T2D with a prospective follow-up from 2002 to 2015. The primary outcome of the current analysis was the first occurrence of PAD, a composite of lower-limb amputation (LLA) or lower-limb revascularization. LLA and lower-limb revascularization were considered individually as secondary outcomes., Results: During a 7-year median follow-up, PAD occurred in 147 (10%) of the 1468 participants. The use of VKAs was not significantly associated with the risk of PAD [multivariable adjusted hazard ratio (HR) 1.42, 95% confidence interval (CI), 0.88-2.31]. During the study period, LLA and lower-limb revascularization occurred in 82 (6%) and 105 (7%) participants, respectively. The use of VKAs was significantly associated with increased risk of LLA [multivariable adjusted HR 1.90 (95% CI, 1.04-3.47)], but not lower-limb revascularization [multivariable adjusted HR 1.08 (95% CI, 0.59-1.97)]., Conclusions: In this prospective study, we did not observe any excess risk of PAD requiring lower-limb revascularization in people with type 2 diabetes using VKAs. However, our data suggest a high risk of LLA in VKA users. Further studies are required to confirm this observation., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Converting natural vegetation for agriculture has resulted in the loss of approximately 5% of the current global terrestrial soil organic carbon (SOC) stock to the atmosphere. Increasing the agricultural area under grassland may reverse some of these losses, but the effectiveness of such a strategy is limited by how quickly SOC recovers after conversion from cropland. Using soil data and extensive land-use histories gathered during the national German agricultural soil inventory, this study aims to answer three questions regarding agricultural land-use change (LUC): (i) how do SOC stocks change with depth following LUC; (ii) how long does it take to reach SOC equilibrium after LUC; and (iii) what is the legacy effect of historic LUC on present day SOC dynamics? By using a novel approach that substitutes space for time and accounts for differences in site properties using propensity score balancing, we determined that sites that were converted from cropland to grassland reached a SOC equilibrium level 47.3% (95% confidence interval (CI): 43.4% to 49.5%) above permanent cropland levels 83 years (95% CI: 79 to 90 years) after conversion. Meanwhile, sites converted from grassland to cropland reached a SOC equilibrium level -33.6% (95% CI: -34.1% to -33.5%) below permanent grassland levels after 180 years (95% CI: 151 to 223 years). We estimate that, over the past century, today's German agricultural soils (16.6 million ha) have gained about 40 million Mg C. Furthermore, croplands with historic LUC from grassland are losing SOC by -0.26 Mg ha -1  year -1 (10% of agricultural land) while grasslands historically converted from cropland are gaining SOC by 0.27 Mg ha -1  year -1 (18% of agricultural land). This study shows that even long-standing temperate agricultural sites likely have ongoing SOC change as a result of historical LUC., (© 2024 The Author(s). Global Change Biology published by John Wiley & Sons Ltd.)

The carbon skeleton of any organic molecule serves as the foundation for its three-dimensional structure, playing a pivotal role in determining its physical and biological properties 1 . As such, taxane diterpenes are one of the most well-known natural product families, primarily owing to the success of their most prominent compound, paclitaxel, an effective anticancer therapeutic for more than 25 years 2-6 . In contrast to classical taxanes, the bioactivity of cyclotaxanes (also referred to as complex taxanes) remains significantly underexplored. The carbon skeletons of these two groups of taxanes differ significantly, and so would typically their own distinct synthetic approaches. Here we report a versatile synthetic strategy based on the interconversion of complex molecular frameworks, providing general access to the wider taxane diterpene family. A range of classical and cyclotaxane frameworks was prepared including, among others, the total syntheses of taxinine K (2), canataxapropellane (5) and dipropellane C from a single advanced intermediate. The synthetic approach deliberately eschews biomimicry, emphasizing instead the power of stereoelectronic control in orchestrating the interconversion of polycyclic frameworks., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Cardiogenic shock (CS) is the most severe form of acute heart failure. Discrepancies have been reported between sexes regarding delays, pathways and invasive strategies in CS complicating acute myocardial infarction. However, effect of sex on the prognosis of unselected CS remains controversial., Objectives: The aim was to analyze the impact of sex on aetiology, management and prognosis of CS., Methods: The FRENSHOCK registry included all CS admitted in 49 French Intensive Care Units (ICU) and Intensive Cardiac Care Units (ICCU) between April and October 2016., Results: Among the 772 CS patients included, 220 were women (28.5%). Women were older, less smokers, with less history of ischemic cardiac disease (20.5% vs 33.6%) than men. At admission, women presented less cardiac arrest (5.5 vs 12.2%), less mottling (32.5 vs 41.4%) and higher LVEF (30 ± 14 vs 25 ± 13%). Women were more often managed via emergency department while men were directly admitted at ICU/ICCU. Ischemia was the most frequent trigger irrespective of sex (36.4% in women vs 38.2%) but women had less coronary angiogram and PCI (45.9% vs 54% and 24.1 vs 31.3%, respectively). We found no major difference in medication and organ support. Thirty-day mortality (26.4 vs 26.5%), transplant or permanent assist device were similar in both sexes., Conclusion: Despite some more favorable parameters in initial presentation and no significant difference in medication and support, women shared similar poor prognosis than men. Further analysis is required to cover the lasting gap in knowledge regarding sex specificities to distinguish between differences and inequalities. NCT02703038., Competing Interests: Declaration of competing interest Manzo-Silberman S has received consulting fees from Bayer, Organon, Exeltis, lecture fees from Bayer, BMS, Exeltis and Organon, has served in the adjudication board for a study for Biotronik. Martin AC has received consulting fees from Alliance BMS-Pfizer, Bayer, grants from Alliance BMS-Pfizer, lecture fees from Alliance BMS-Pfizer, Abbott, Bayer, Novartis. Boissier.F has received travel and accomodation fees from AOP Orphan. Leurent.G reports proctoring activity, lecture and consultant fees from Abbott. Combaret N has received lecture fees from Pfizer and Medtronic. Gerbaud E has received consulting fees from Terumo, Abbott and Vifor phama. Delmas C has received consulting fees from Abiomed, Abbott and Moderna; lecture fees from Abiomed, Abott, Astrazeneca, Bayer, Orion and Servier. All the other authors have nothing to disclaimed., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The mechanism that causes the rapid uplift and active magmatism of the Hoh-Xil Basin in the northern Tibetan Plateau and hence the outward growth of the proto-plateau is highly debated, more specifically, over the relationship between deep dynamics and surface uplift. Until recently the Hoh-Xil Basin remained uncovered by seismic networks due to inaccessibility. Here, based on linear seismic arrays across the Hoh-Xil Basin, we present a three-dimensional S-wave velocity (V S ) model of the crust and uppermost mantle structure beneath the Tibetan Plateau from ambient noise tomography. This model exhibits a widespread partially molten crust in the northern Tibetan Plateau but only isolated pockets in the south manifested as low-V S anomalies in the middle crust. The spatial correlation of the widespread low-V S anomalies with strong uppermost mantle low-V S anomalies and young exposed magmatic rocks in the Hoh-Xil Basin suggests that the plateau grew through lithospheric mantle removal and its driven magmatism., (© The Author(s) 2024. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.)

Background: POINCARE-2 trial aimed to assess the effectiveness of a strategy designed to tackle fluid overload through daily weighing and subsequent administration of treatments in critically ill patients. Even in highly standardized care settings, such as intensive care units, effectiveness of such a complex intervention depends on its actual efficacy but also on the extent of its implementation. Using a process evaluation, we aimed to provide understanding of the implementation, context, and mechanisms of change of POINCARE-2 strategy during the trial, to gain insight on its effectiveness and inform the decision regarding the dissemination of the intervention., Methods: We conducted a mixed-method process evaluation following the Medical Research Council guideline. Both quantitative data derived from the trial, and qualitative data from semi-structured interviews with professionals were used to explain implementation, mechanisms of change of the POINCARE-2 strategy, as well as contextual factors potentially influencing implementation of the strategy., Results: Score of actual exposure to the strategy ranged from 29.1 to 68.2% during the control period, and from 61.9 to 92.3% during the intervention period, suggesting both potential contamination and suboptimal fidelity to the strategy. Lack of appropriate weighing devices, lack of human resources dedicated to research, pre-trial rooted prescription habits, and anticipated knowledge of the strategy have been identified as the main barriers to optimal implementation of the strategy in the trial context., Conclusions: Both contamination and suboptimal fidelity to POINCARE-2 strategy raised concerns about a potential bias towards the null of intention-to-treat (ITT) analyses. However, optimal fidelity seemed reachable. Consequently, a clinical strategy should not be rejected solely on the basis of the negativity of ITT analyses' results. Our findings showed that, even in highly standardized care conditions, the implementation of clinical strategies may be hindered by numerous contextual factors, which demonstrates the critical importance of assessing the viability of an intervention, prior to any evaluation of its effectiveness., Trial Registration: Number NCT02765009., (© 2024. The Author(s).)

Context: Neurohypophysis (NH) function in eating disorders (ED) remains poorly elucidated. Studies on vasopressin and oxytocin display inconclusive findings regarding their levels and associations with psychological complications in ED. The profile of opioid tone, a crucial NH activity regulator, is also unknown., Objective: To characterise the circadian profile of NH hormones and NH opioid tone using positron emission tomography/MRI (PET/MRI) imaging in patients with ED compared to healthy controls., Methods: Twelve-point plasma circadian profiles of copeptin and oxytocin, alongside nutritional and psychological scores, were assessed in age-matched female participants: 13 patients with anorexia nervosa restrictive-type (ANR), 12 patients recovered from AN (ANrec), 14 patients with bulimia nervosa and 12 controls. Neurohypophysis PET/MRI [ 11 C] diprenorphin binding potential (BP ND ) was evaluated in AN, ANrec and controls., Results: Results revealed lower copeptin circadian levels in both ANR and ANrec compared to controls, with no oxytocin differences. Bulimia nervosa exhibited elevated copeptin and low oxytocin levels. [ 11 C] diprenorphin pituitary binding was fully localised in NH. Anorexia nervosa restrictive-type displayed lower NH [ 11 C] diprenorphin BP ND (indicating higher opioid tone) and volume than controls. In ANR, copeptin inversely correlated with osmolarity. Neurohypophysis [ 11 C] diprenorphin BP ND did not correlated with copeptin or oxytocin., Conclusion: Copeptin demonstrated significant group differences, highlighting its potential diagnostic and prognostic value. Oxytocin levels exhibited conflicting results, questioning the reliability of peripheral blood assessment. Increased NH opioid tone in anorexia nervosa may influence the vasopressin or oxytocin release, suggesting potential therapeutic applications., (© 2024 The Author(s). European Eating Disorders Review published by Eating Disorders Association and John Wiley & Sons Ltd.)

Background: Critical-illness survivors may experience post-traumatic stress disorder (PTSD) and quality-of-life impairments. Resilience may protect against psychological trauma but has not been adequately studied after critical illness. We assessed resilience and its associations with PTSD and quality of life, and also identified factors associated with greater resilience., Methods: This prospective, multicentre, study in patients recruited at 41 French ICUs was done in parallel with the NUTRIREA-3 trial in patients given mechanical ventilation and vasoactive amines for shock. Three months to one year after intensive-care-unit admission, survivors completed the Connor-Davidson Resilience Scale (CD-RISC-25), Impact of Event-Revised scale for PTSD symptoms (IES-R), SF-36 quality-of-life scale, Multidimensional Scale of Perceived Social Support (MSPSS), and Brief Illness Perception Questionnaire (B-IPQ)., Results: Of the 382 included patients, 203 (53.1%) had normal or high resilience (CD-RISC-25 ≥ 68). Of these resilient patients, 26 (12.8%) had moderate to severe PTSD symptoms (IES-R ≥ 24) vs. 45 (25.4%) patients with low resilience (p = 0.002). Resilient patients had higher SF-36 scores. Factors independently associated with higher CD-RISC-25 scores were higher MSPSS score indicating stronger social support (OR, 1.027; 95%CI 1.008-1.047; p = 0.005) and lower B-IPQ scores indicating a more threatening perception of the illness (OR, 0.973; 95%CI 0.950-0.996; p = 0.02)., Conclusions: Resilient patients had a lower prevalence of PTSD symptoms and higher quality of life scores, compared to patients with low resilience. Higher scores for social support and illness perception were independently associated with greater resilience. Thus, our findings suggest that interventions to strengthen social support and improve illness perception may help to improve resilience. Such interventions should be evaluated in trials with PTSD mitigation and quality-of-life improvement as the target outcomes., (© 2024. The Author(s).)

Introduction: The primary aim of this study was to evaluate the clinical and radiological outcomes after surgical treatment of proximal femoral fractures utilizing the Proximal Femoral Nail Antirotation (PFNA), with the main focus on complications and reoperations. The secondary aim was to compare the outcomes of patients with and without cement augmentation of the cephalomedullary nails., Materials and Methods: All patients with an acute proximal femoral fracture consequently treated with a PFNA between January 2011 and Dezember  2018 were evaluated. Clinical and radiological data were assessed for intra- and postoperative complications, including treatment failure. In addition, intra- and postoperative radiographs were used to determine the position of the implant, and any migration, via Tip-Apex-Distance (TAD) and the caput-collum-diaphyseal angle (CCD). The accuracy of the fracture reduction was rated according to Baumgaertners criteria., Results: Two hundred sixty-four consecutive patients (mean age 78.8 ± 12.0; 73.1% female) were included. The predominant OTA/AO fracture classification was 31A1 (153 cases, 58.0%). The average duration of surgery was 63.1 ± 28.0 min and showed no significant differences between PFNA and PFNA with augmentation. The implant positioning was rated as good in 222 cases (84.1%). Two hundred sixty-three patients (99.6%) showed evidence of healing within the time frame of three months postoperatively, one case of delayed union healed after secondary dynamization. During the observational period, 18 patients (6.8%) required a total of 23 additional surgeries. Overall, a lower reoperation rate was observed following the use of the augmentation option (2/86 patients (2.3%) vs. 16/178 patients (9.0%), p = 0.04). In particular, there were no cases of cut-out or cut-through among patients who underwent augmentation as part of osteosynthesis., Conclusions: Overall reoperation rate after surgical treatment of proximal femoral fractures utilizing the Proximal Femoral Nail Antirotation (PFNA) was 6.8%, with 23 additional surgeries performed in 18 patients. The usage of the PFNA with augmentation showed equally good implant positioning, excellent healing rates and fewer postoperative complications compared to the PFNA implant alone with a similar overall duration of surgery., (© 2024. The Author(s).)

Background: Mobile health (mHealth) apps offer unique opportunities to support self-care and behavior change, but poor user engagement limits their effectiveness. This is particularly true for fully automated mHealth apps without any human support. Human support in mHealth apps is associated with better engagement but at the cost of reduced scalability., Objective: This work aimed to (1) describe the theory-informed development of a fully automated relaxation and mindfulness app to reduce distress in people with cancer (CanRelax app 2.0), (2) describe engagement with the app on multiple levels within a fully automated randomized controlled trial over 10 weeks, and (3) examine whether engagement was related to user characteristics., Methods: The CanRelax app 2.0 was developed in iterative processes involving input from people with cancer and relevant experts. The app includes evidence-based relaxation exercises, personalized weekly coaching sessions with a rule-based conversational agent, 39 self-enactable behavior change techniques, a self-monitoring dashboard with gamification elements, highly tailored reminder notifications, an educational video clip, and personalized in-app letters. For the larger study, German-speaking adults diagnosed with cancer within the last 5 years were recruited via the web in Switzerland, Austria, and Germany. Engagement was analyzed in a sample of 100 study participants with multiple measures on a micro level (completed coaching sessions, relaxation exercises practiced with the app, and feedback on the app) and a macro level (relaxation exercises practiced without the app and self-efficacy toward self-set weekly relaxation goals)., Results: In week 10, a total of 62% (62/100) of the participants were actively using the CanRelax app 2.0. No associations were identified between engagement and level of distress at baseline, sex assigned at birth, educational attainment, or age. At the micro level, 71.88% (3520/4897) of all relaxation exercises and 714 coaching sessions were completed in the app, and all participants who provided feedback (52/100, 52%) expressed positive app experiences. At the macro level, 28.12% (1377/4897) of relaxation exercises were completed without the app, and participants' self-efficacy remained stable at a high level. At the same time, participants raised their weekly relaxation goals, which indicates a potential relative increase in self-efficacy., Conclusions: The CanRelax app 2.0 achieved promising engagement even though it provided no human support. Fully automated social components might have compensated for the lack of human involvement and should be investigated further. More than one-quarter (1377/4897, 28.12%) of all relaxation exercises were practiced without the app, highlighting the importance of assessing engagement on multiple levels., (©Sonja Schläpfer, Fabian Schneider, Prabhakaran Santhanam, Manuela Eicher, Tobias Kowatsch, Claudia M Witt, Jürgen Barth. Originally published in JMIR Cancer (https://cancer.jmir.org), 31.05.2024.)

In the context of breast cancer treatment optimization, this study prospectively examines the feasibility and outcomes of utilizing intraoperative radiotherapy (IORT) as a boost in combination with standard external beam radiotherapy (EBRT) for high-risk patients. Different guidelines recommend such a tumor bed boost in addition to whole breast irradiation with EBRT for patients with risk factors for local breast cancer recurrence. The TARGIT BQR (NCT01440010) is a prospective, multicenter registry study aimed at ensuring the quality of clinical outcomes. It provides, for the first time, data from a large cohort with a detailed assessment of acute and long-term toxicity following an IORT boost using low-energy X-rays. Inclusion criteria encompassed tumors up to 3.5 cm in size and preoperative indications for a boost. The IORT boost, administered immediately after tumor resection, delivered a single dose of 20 Gy. EBRT and systemic therapy adhered to local tumor board recommendations. Follow-up for toxicity assessment (LENT SOMA criteria: fibrosis, teleangiectasia, retraction, pain, breast edema, lymphedema, hyperpigmentation, ulceration) took place before surgery, 6 weeks to 90 days after EBRT, 6 months after IORT, and then annually using standardized case report forms (CRFs). Between 2011 and 2020, 1133 patients from 10 centers were preoperatively enrolled. The planned IORT boost was conducted in 90%, and EBRT in 97% of cases. Median follow-up was 32 months (range 1-120, 20.4% dropped out), with a median age of 61 years (range 30-90). No acute grade 3 or 4 toxicities were observed. Acute side effects included erythema grade 1 or 2 in 4.4%, palpable seroma in 9.1%, punctured seroma in 0.3%, and wound healing disorders in 2.1%. Overall, chronic teleangiectasia of any grade occurred in 16.2%, fibrosis grade ≥ 2 in 14.3%, pain grade ≥ 2 in 3.4%, and hyperpigmentation in 1.1%. In conclusion, a tumor bed boost through IORT using low-energy X-rays is a swift and feasible method that demonstrates low rates in terms of acute or long-term toxicity profiles in combination with whole breast irradiation.

Introduction: Deficits in emotion recognition and processing are characteristic for patients with schizophrenia [SCZ]., Methods: We targeted both emotion recognition and affective sharing, one in static and one in dynamic facial stimuli, during functional magnetic resonance imaging [fMRI] in 22 SCZ patients and 22 matched healthy controls [HC]. Current symptomatology and cognitive deficits were assessed as potential influencing factors., Results: Behaviorally, patients only showed a prolonged response time in age-discrimination trials. For emotion-processing trials, patients showed a difference in neural response, without an observable behavioral correlate. During emotion and age recognition in static stimuli, a reduced activation of the bilateral anterior cingulate cortex [ACC] and the right anterior insula [AI] emerged. In the affective sharing task, patients showed a reduced activation in the left and right caudate nucleus, right AI and inferior frontal gyrus [IFG], right cerebellum, and left thalamus, key areas of empathy., Discussion: We conclude that patients have deficits in complex visual information processing regardless of emotional content on a behavioral level and that these deficits coincide with aberrant neural activation patterns in emotion processing networks. The right AI as an integrator of these networks plays a key role in these aberrant neural activation patterns and, thus, is a promising candidate area for neurofeedback approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Knobloch, Leiding, Wagels, Regenbogen, Kellermann, Mathiak, Schneider, Derntl and Habel.)

Microplastics pose a significant environmental threat, with potential implications for toxic chemical release, aquatic life endangerment, and human food chain contamination. In Asia, rapid economic growth coupled with inadequate waste management has escalated plastic pollution in rivers, positioning them as focal points for environmental concern. Despite Asia's rivers being considered the most polluted with plastics globally, scholarly attention to microplastics in the region's freshwater environments is a recent development. This study undertakes a systematic review of 228 scholarly articles to map microplastic hotspots in Asian freshwater systems and synthesize current research trends within the continent. Findings reveal a concentration of research in China and Japan, primarily investigating riverine and surface waters through net-based sampling methods. Polyethylene (PE), polypropylene (PP), and polyethylene terephthalate (PET) emerge as the predominant microplastic types, frequently observed as fibers or fragments. However, the diversity of sampling methodologies and reporting metrics complicates data synthesis, underscoring the need for standardized analytical frameworks to facilitate comparative analysis. This paper delineates the distribution of microplastic hotspots and outlines the prevailing challenges and prospects in microplastic research within Asian freshwater contexts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The 8.4 eV nuclear isomer state in Th-229 is resonantly excited in Th-doped CaF&#95;{2} crystals using a tabletop tunable laser system. A resonance fluorescence signal is observed in two crystals with different Th-229 dopant concentrations, while it is absent in a control experiment using Th-232. The nuclear resonance for the Th^{4+} ions in Th:CaF&#95;{2} is measured at the wavelength 148.3821(5) nm, frequency 2020.409(7) THz, and the fluorescence lifetime in the crystal is 630(15) s, corresponding to an isomer half-life of 1740(50) s for a nucleus isolated in vacuum. These results pave the way toward Th-229 nuclear laser spectroscopy and realizing optical nuclear clocks.

Objective: Antibiotic resistance (ABR) is a major threat to public health. Hospital healthcare professionals are important stakeholders in curbing ABR. To be able to encourage healthcare professionals to act against ABR, information on their perceptions is needed. Yet, summary evidence on how healthcare professionals perceive ABR causes, consequences, and solutions is outdated. This review aims to elucidate these perceptions., Methods: We searched MEDLINE, EMBASE, PsycINFO, and CINAHL for literature published until July 6th, 2022, and used Web of Science and Scopus to identify reports citing included studies. Reports of quantitative original research from high-income countries were included if they investigated hospital healthcare professionals' perceptions about ABR. Descriptive data and data on perceptions about causes, consequences, and solutions regarding ABR were extracted. PROSPERO registration: CRD42022359249., Results: The database search and citation tracking yielded 13,551 and 694 papers respectively. Forty-eight reports from 46 studies were included in the review. These studies were performed between 1999 and 2023 and included between 8 and 1362 participants. Healthcare professionals perceived ABR as a problem that is more severe nationally than locally and they primarily recognize ABR as a distant and abstract problem. Studies mostly concurred on prescribing behavior as a cause and a solution for ABR, while external causes and solutions (e.g., in agriculture) elicited less agreement., Conclusions: Studies with a primary focus on the perceptions of healthcare professionals about ABR are limited. Healthcare professionals perceive prescribing behavior as a major cause of ABR and a focus area for ABR solutions., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Desorption of molecules from surfaces is widespread both in nature and technology. Despite its omnipresence and conceptual simplicity, fundamental details can be surprisingly complex and are often poorly understood. In many cases, first-order kinetics is assumed, which implies that the adsorbates do not interact with each other and desorption is the rate-limiting process. While this might be a good approximation in some cases, it is far from reality in the case of adsorbates that form ordered structures. Here, we study the desorption of a submonolayer film of 3-nitrophenol from the natural cleavage plane of calcite kept in ultrahigh vacuum. Interestingly, two distinctly different desorption regimes are observed during isothermal desorption monitored by dynamic atomic force microscopy. Initially, at high coverages, the coverage decreases almost linearly in time, indicating a constant desorption rate. Beyond this linear regime, at low coverages, a drastic increase in desorption rate is observed until the surface is completely empty. The transition between these two regimes is associated with a critical island width. We propose an existence of a long-range attractive interaction between the molecules as a possible explanation for the sudden increase in the desorption rate when a critical island width is reached. The herein observed phenomenon of two different desorption regimes is expected to be of general nature when interactions beyond next-neighbour attraction are present.

Massive stars (those ≥8 solar masses at formation) have radiative envelopes that cannot sustain a dynamo, the mechanism that produces magnetic fields in lower-mass stars. Despite this, approximately 7% of massive stars have observed magnetic fields, the origin of which is debated. We used multi-epoch interferometric and spectroscopic observations to characterize HD 148937, a binary system of two massive stars. We found that only one star is magnetic and that it appears younger than its companion. The system properties and a surrounding bipolar nebula can be reproduced with a model in which two stars merged (in a previous triple system) to produce the magnetic massive star. Our results provide observational evidence that magnetic fields form in at least some massive stars through stellar mergers.

Background: Antimicrobial resistance is a major global health threat. Therefore, promising new antibacterial technologies that could minimize our dependence on antibiotics should be widely adopted. This study aims to identify the barriers and facilitators of the adoption of new antibacterial technologies in hospital patient care., Methods: Semi-structured interviews, based on the Consolidated Framework for Implementation Research, were conducted with healthcare professionals related to the orthopedics department of an academic hospital in The Netherlands., Results: In total, 11 healthcare professionals were interviewed. Scientific evidence for the effectiveness of the technology was the most explicitly mentioned facilitator of adoption, but other (often contextual) factors were also considered to be important. At the level of the inner and outer setting, high costs and lacking coverage, competition from other firms, and problems with ordering and availability were the most explicit perceived barriers to adoption. Participants did not collectively feel the need for new antibacterial technologies., Conclusions: Barriers and facilitators of the adoption of new antibacterial technologies were identified related to the technology, the hospital, and external factors. The implementation climate might have an indirect influence on adoption. New antibacterial technologies that are scientifically proven effective, affordable, and easily obtainable will most likely be adopted., (© 2024. The Author(s).)

Background: Likewise work experience, heart rate variability (HRV) has repeatedly been correlated with improved performance under real life and simulator conditions. Using HRV as a correlate of workload, it is meaningful to assess the impact of work experience. To understand the impact of work experience on HRV metrics, we examined differences in HRV among experts and beginners during simulated endovascular neuroradiological procedures., Methods: Six inexperienced radiologists (beginners) and five experts in neurological endovascular intervention each performed 10 diagnostic angiographies on a Vascular Interventional System Trainer (VIST) simulator (Mentice AB, SW). Beyond total time, fluoroscopy time, and amount of contrast medium used, heart rate variability and the NASA-task load index were gathered as correlates of workload. The t-Test for independent samples as well as Mann-Whitney-U tests were applied for group-wise comparison between beginners and experts. Multivariate regression was used to assess the influence of age and expert status., Results: Ten participants completed all scenarios; one participant only completed the first five scenarios. Accordingly, 105 simulations were analyzed (beginners N = 60; experts N = 45, respectively). The heart rate variability of experts and beginners significantly differed in three time domain HRV metrics (decreased RMSSD, NN50, pNN50 in experts; all p < 0.05) as well as with respect to its distribution in the frequency spectrum (LF/HF ratio; p < 0.001, increased high frequency components in experts)., Conclusions: The HRV of beginners and expert neurointerventionalists significantly differed during simulated endovascular neuroradiological procedures. Experts presented decreased HRV, this could be a cardiovascular surrogate to the effort the subjects expend on their performance. It is in line with previous studies on vagal influences on the heart and cognitive-executive performance., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: A profound transformation of all areas of human activities is urgently needed for planetary health. Developing a shared vision of the future that is grounded in values aligned with planetary health is indispensable in this regard. The Planetary Health Academy is the first open online lecture series in Germany aiming for transformative planetary health education. As part of a recent evaluation of the impact of the lecture series, participants' visions for planetary health were also examined., Methods: As part of a retrospective, cross-sectional, self-administered online survey, participants were asked to respond to an open-ended question on their visions for planetary health. Results were analysed using summarising qualitative content analysis according to Mayring. Sociodemographic details of those participants who provided a valid answer (n = 197) were calculated., Results: Eight main categories were developed to summarise participants' visions for planetary health. These were: Awareness for planetary health - Planetary health integrated in all types of education - Establishment and development of the concept - A different understanding of health (care) - A transformative movement and global community - Transforming human activities - Planetary health as a guiding principle - The future state of planetary health., Discussion: Broadly, the participants' visions were about planetary health as a goal and the means necessary to achieve this goal. Our findings can only be seen as a first explorative step in eliciting aspects of a common vision for planetary health, as our study design did not include a mechanism of building consensus towards one common vision. Besides the field of planetary health, similar concepts and associated movements exist or are emerging. Facilitating dialogue and exchange across disciplines and narratives about the prevailing future visions will be key to achieving what we call planetary health and what others might call Ubuntu or buen vivir., Conclusion: The results of this study provide first insights into the planetary health visions of those whom we would consider members of a movement aligned behind the idea of planetary health. In future editions, the Planetary Health Academy could integrate more discursive elements with a particular focus on negotiating future visions to support the creation of a critical mass of change agents within the health community and beyond., (Copyright © 2024. Published by Elsevier GmbH.)

Evidence for the effectiveness of physical activity (PA) in the treatment of depression prevails for outpatients with mild and moderate symptom levels. For inpatient treatment of severe depression, evidence-based effectiveness exists only for structured and supervised group PA interventions. The Step Away from Depression (SAD) study investigated the effectiveness of an individual pedometer intervention (PI) combined with an activity diary added to inpatient treatment as usual (TAU). In this multicenter randomized controlled trial, 192 patients were randomized to TAU or TAU plus PI. The two primary outcomes at discharge were depression-blindly rated with the Montgomery-Åsberg Depression Rating Scale (MADRS)-and average number of daily steps measured by accelerometers. Secondary outcomes were self-rated depression and PA, anxiety, remission and response rates. Multivariate analysis of variance (MANOVA) revealed no significant difference between both groups for depression and daily steps. Mean MADRS scores at baseline were 29.5 (SD = 8.3) for PI + TAU and 28.8 (SD = 8.1) for TAU and 16.4 (SD = 10.3) and 17.2 (SD = 9.9) at discharge, respectively. Daily steps rose from 6285 (SD = 2321) for PI + TAU and 6182 (SD = 2290) for TAU to 7248 (SD = 2939) and 7325 (SD = 3357). No differences emerged between groups in secondary outcomes. For severely depressed inpatients, a PI without supervision or further psychological interventions is not effective. Monitoring, social reinforcement and motivational strategies should be incorporated in PA interventions for this population to reach effectiveness., (© 2023. The Author(s).)

Background: Due to aging population and increasing part of immunocompromised patients, a raise in life-threatening organ damage related to VZV can be expected. Two retrospective studies were already conducted on VZV in ICU but focused on specific organ injury. Patients with high-risk of VZV disease still must be identified. The objective of this study was to report the clinical features and outcome of all life-threatening VZV manifestations requiring intensive care unit (ICU) admission. This retrospective cohort study was conducted in 26 French ICUs and included all adult patients with any life-threatening VZV-related event requiring ICU admission or occurring in ICU between 2010 and 2019., Results: One-hundred nineteen patients were included with a median SOFA score of 6. One hundred eight patients (90.8%) were admitted in ICU for VZV disease, leaving 11 (9.2%) with VZV disease occurring in ICU. Sixty-one patients (51.3%) were immunocompromised. Encephalitis was the most prominent organ involvement (55.5%), followed by pneumonia (44.5%) and hepatitis (9.2%). Fifty-four patients (45.4%) received norepinephrine, 72 (60.5% of the total cohort) needed invasive mechanical ventilation, and 31 (26.3%) received renal-replacement therapy. In-hospital mortality was 36.1% and was significantly associated with three independent risk factors by multivariable logistic regression: immunosuppression, VZV disease occurring in ICU and alcohol abuse. Hierarchical clustering on principal components revealed five phenotypically distinct clusters of patients: VZV-related pneumonia, mild encephalitis, severe encephalitis in solid organ transplant recipients, encephalitis in other immunocompromised hosts and VZV disease occurring in ICU. In-hospital mortality was highly different across phenotypes, ranging from zero to 75% (p < 0.001)., Conclusion: Overall, severe VZV manifestations are associated with high mortality in the ICU, which appears to be driven by immunosuppression status rather than any specific organ involvement. Deciphering the clinical phenotypes may help clinicians identify high-risk patients and assess prognosis., (© 2024. The Author(s).)

For generations researchers have been observing the dynamic processes of life through the lens of a microscope. This has offered tremendous insights into biological phenomena that span multiple orders of time- and length-scales ranging from the pure magic of molecular reorganization at the membrane of immune cells, to cell migration and differentiation during development or wound healing. Standard fluorescence microscopy techniques offer glimpses at such processes in vitro, however, when applied in intact systems, they are challenged by reduced signal strengths and signal-to-noise ratios that result from deeper imaging. As a remedy, two-photon excitation (TPE) microscopy takes a special place, because it allows us to investigate processes in vivo, in their natural environment, even in a living animal. Here, we review the fundamental principles underlying TPE aimed at basic and advanced microscopy users interested in adopting TPE for intravital imaging. We focus on applications in neurobiology, present current trends towards faster, wider and deeper imaging, discuss the combination with photon counting technologies for metabolic imaging and spectroscopy, as well as highlight outstanding issues and drawbacks in development and application of these methodologies., (© 2024. The Author(s).)

The first total synthesis of the potent antimicrobial agent dynobactin A is disclosed. This synthesis enlists a singular aziridine ring opening strategy to access the two disparate β-aryl-branched amino acids present within this complex decapeptide. Featuring a number of unique maneuvers to navigate inherently sensitive and epimerizable functional groups, this convergent approach proceeds in only 16 steps (LLS) from commercial materials and should facilitate the synthesis of numerous analogues for medicinal chemistry studies.

Introduction: This study aimed to determine the body accelerations (BA) profile of the judo contest of the male and female weight divisions and to ascertain the involvement of the vertical, mediolateral and anteroposterior axes in it., Methods: Forty-eight male and forty-eight female national and international level athletes (some of them medalists in World, European and national championships) participated in a 5-min simulated contest (official fight time plus breaks) against an opponent of the same sex and weight division, wearing an accelerometer. Heart rate, blood lactate and ratings of perceived exertion were recorded to certify that the athletes performed the fullest., Results: The t2way test expressed differences in the athletes' BA ( p = 0.001) and three profiles were identified: the light/middle weight male divisions, the light/middle weight female divisions and the heavy male and female ones. Athletes of all weight divisions performed their BA during the contest in all three directions (the one-sample Person's chi-square did not detect any significantly predominant one: p = 0.400, p = 0.631, p = 0.844, p = 0.749, p = 0.644 and p = 0.895, for male light, moderate and heavy, female light, moderate and heavyweight athletes, respectively). Monte Carlo method simulations suggested as the most likely scenarios those with BA involving all axes, with a slight preference of the anteroposterior and mediolateral ones., Discussion: These results suggest that the demands on judo athletes in a contest differ between weight classes and sexes., 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 Santos, Federolf, Schneider, Pocecco, Fernández-Río, Iglesias-Soler, Carballeira-Fernández, Uriarte and Dopico-Calvo.)

Background: The effects of pharmacological therapy on cardiogenic shock (CS) survivors have not been extensively studied. Thus, this study investigated the association between guideline-directed heart failure (HF) medical therapy (GDMT) and one-year survival rate in patients who are post-CS., Methods and Results: FRENSHOCK (French Observatory on the Management of Cardiogenic Shock in 2016) registry was a prospective multicenter observational survey, conducted in metropolitan French intensive care units and intensive cardiac care units. Of 772 patients, 535 patients were enrolled in the present analysis following the exclusion of 217 in-hospital deaths and 20 patients with missing medical records. Patients with triple GDMT (beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists) at discharge (n=112) were likely to have lower left ventricular ejection fraction on admission and at discharge compared with those without triple GDMT (n=423) (22% versus 28%, P <0.001 and 29% versus 37%, P <0.001, respectively). In the overall cohort, the one-year mortality rate was 23%. Triple GDMT prescription was significantly associated with a lower one-year all-cause mortality compared with non-triple GDMT (adjusted hazard ratio 0.44 [95% CI, 0.19-0.80]; P =0.007). Similarly, 2:1 propensity score matching and inverse probability treatment weighting based on the propensity score demonstrated a lower incidence of one-year mortality in the triple GDMT group. As the number of HF drugs increased, a stepwise decrease in mortality was observed (log rank; P <0.001)., Conclusions: In survivors of CS, the one-year mortality rate was significantly lower in those with triple GDMT. Therefore, this study suggests that intensive HF therapy should be considered in patients following CS.

Compounds with multiple photoswitching units are appealing for complex photochemical control of molecular materials and nanostructures. Herein, we synthesized novel meta- and para- connected (related to the nitrogen of the indoline) azobenzene-spiropyran dyads, in which the central benzene unit is shared by both switches. We investigated their photochemistry using static and time-resolved transient absorption spectroscopy as well as quantum chemical calculations. In the meta-compound, the individual components are photochemically decoupled due to the meta-pattern. In the para-compound the spiro-connectivity leads to a bifunctional photoswitchable system with a red-shifted absorption. The azobenzene and the spiropyran can thus be addressed and switched independently by light of appropriate wavelength. Through the different connectivity patterns two different orthogonally photoswitchable systems have been obtained which are promising candidates for complex applications of light control., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)