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Background and Objective: Cerebral vascular diseases are among the most burdensome diseases faced by society. However, investigating the pathophysiology of diseases as well as developing future treatments still relies heavily on expensive in-vivo and in-vitro studies. The generation of realistic, patient-specific models of the cerebrovascular system capable of simulating hemodynamics and perfusion promises the ability to simulate diseased states, therefore accelerating development cycles using in silico studies and opening opportunities for the individual assessment of diseased states, treatment planning, and the prediction of outcomes. By providing a patient-specific, anatomically detailed and validated model of the human cerebral vascular system, we aim to provide the basis for future in silico investigations of the cerebral physiology and pathology., Methods: In this retrospective study, a processing pipeline for patient-specific quantification of cerebral perfusion was developed and applied to healthy individuals and a stroke patient. Major arteries are segmented from 3T MR angiography data. A synthetic tree generation algorithm titled tissue-growth based optimization (GBO) 1 is used to extend vascular trees beyond the imaging resolution. To investigate the anatomical accuracy of the generated trees, morphological parameters are compared against those of 7 T MRI, 9.4 T MRI, and dissection data. Using the generated vessel model, hemodynamics and perfusion are simulated by solving one-dimensional blood flow equations combined with Darcy flow equations., Results: Morphological data of three healthy individuals (mean age 47 years ± 15.9 [SD], 2 female) was analyzed. Bifurcation and physiological characteristics of the synthetically generated vessels are comparable to those of dissection data. The inability of MRI based segmentation to resolve small branches and the small volume investigated cause a mismatch in the comparison to MRI data. Cerebral perfusion was estimated for healthy individuals and a stroke patient. The simulated perfusion is compared against Arterial-Spin-Labeling MRI perfusion data. Good qualitative agreement is found between simulated and measured cerebral blood flow (CBF) 2 . Ischemic regions are predicted well, however ischemia severity is overestimated., Conclusions: GBO successfully generates detailed cerebral vascular models with realistic morphological parameters. Simulations based on the resulting networks predict perfusion territories and ischemic regions successfully., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19)., Methods: NAPKON-HAP is a multi-centered prospective observational study with a long-term follow-up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients., Results: Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research., Conclusion: NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity., (© 2023. The Author(s).)

Testicular adrenal rest tumors and adrenogenital syndrome (AGS) - Do not mix up with malignant testicular tumors! Testicular adrenal residual tumors (TARTs) frequently occur in men with adrenogenital syndrome. Without knowledge of AGS, diagnosis is problematic due to difficult differentiation from other testicular tumors. However, early treatment is crucial for maintaining or regaining fertility, among other aspects. This article provides background knowledge for general practitioners., (© 2024. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objectives: The gut microbiota can mediate both pro and anti-inflammatory responses. In patients with psoriatic arthritis (PsA), we investigated the impact of faecal microbiota transplantation (FMT), relative to sham transplantation, on 92 inflammation-associated plasma proteins., Methods: This study relates to the FLORA trial cohort, where 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate treatment, were included in a 26-week, double-blind, randomised, sham-controlled trial. Participants were allocated to receive either one gastroscopic-guided healthy donor FMT (n=15) or sham (n=16). Patient plasma samples were collected at baseline, week 4, 12 and 26 while samples from 31 age-matched and sex-matched healthy controls (HC) were collected at baseline. Samples were analysed using proximity extension assay technology (Olink Target-96 Inflammation panel)., Results: Levels of 26 proteins differed significantly between PsA and HC pre-FMT (adjusted p<0.05), of which 10 proteins were elevated in PsA: IL-6, CCL20, CCL19, CDCP1, FGF-21, HGF, interferon-γ (IFN-γ), IL-18R1, monocyte chemotactic protein 3, and IL-2. In the FMT group, levels of 12 proteins changed significantly across all timepoints (tumour necrosis factor (TNF), CDCP1, IFN-γ, TWEAK, signalling lymphocytic activation molecule (SLAMF1), CD8A, CD5, Flt3L, CCL25, FGF-23, CD6, caspase-8). Significant differences in protein levels between FMT and sham-treated patients were observed for TNF (p=0.002), IFN-γ (p=0.011), stem cell factor (p=0.024), matrix metalloproteinase-1 (p=0.038), and SLAMF1 (p=0.042). FMT had the largest positive effect on IFN-γ, Axin-1 and CCL25 and the largest negative effect on CCL19 and IL-6., Conclusions: Patients with active PsA have a distinct immunological plasma protein signature compared with HC pre-FMT. FMT affects several of these disease markers, including sustained elevation of IFN-γ., Trial Registration Number: NCT03058900., Competing Interests: Competing interests: BHM has received consultancy fees from Finch Therapeutics Group, outside of the submitted work. JRM has received consultancy fees from Cultech Ltd., and Enterobiotix Ltd., outside of the submitted work., (© 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.)

Neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism, involve altered synaptic transmission and plasticity. Functional characterization of their associated genes is vital for understanding physio-pathological brain functions. LGI3 is a recently recognized ID-associated gene encoding a secretory protein related to an epilepsy-gene product, LGI1. Here, we find that LGI3 is uniquely secreted from oligodendrocytes in the brain and enriched at juxtaparanodes of myelinated axons, forming nanoscale subclusters. Proteomic analysis using epitope-tagged Lgi3 knockin mice shows that LGI3 uses ADAM23 as a receptor and selectively co-assembles with Kv1 channels. A lack of Lgi3 in mice disrupts juxtaparanodal clustering of ADAM23 and Kv1 channels and suppresses Kv1-channel-mediated short-term synaptic plasticity. Collectively, this study identifies an extracellular organizer of juxtaparanodal Kv1 channel clustering for finely tuned synaptic transmission. Given the defective secretion of the LGI3 missense variant, we propose a molecular pathway, the juxtaparanodal LGI3-ADAM23-Kv1 channel, for understanding neurodevelopmental disorders., Competing Interests: Declaration of interests T.E. is the founder and researcher at Phenovance, LLC, Japan., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

In steroid-responsive meningitis-arteritis (SRMA), inflammatory dysregulation is driven by neutrophilic granulocytes resulting in purulent leptomeningitis. Neutrophils can generate neutrophil extracellular traps (NET). Uncontrolled NET-formation or impaired NET-clearance evidently cause tissue and organ damage resulting in immune-mediated diseases. The aim of the study was to verify that NET-formation is detectable in ex vivo samples of acute diseased dogs with SRMA by visualizing and measuring NET-markers in serum and cerebrospinal fluid (CSF) samples. CSF-samples of dogs with acute SRMA (n = 5) and in remission (n = 4) were examined using immunofluorescence (IF)-staining of DNA-histone-1-complexes, myeloperoxidase and citrullinated Histone H3 (H3Cit). Immunogold-labeling of H3Cit and neutrophil elastase followed by transmission electron microscopy (TEM) were used to determine ultrastructural NET-formation in the CSF of one exemplary dog. H3Cit-levels and DNase-activity were measured in CSF and serum samples using an H3Cit-ELISA and a DNase-activity-assay, respectively in patients with the following diseases: acute SRMA (n = 34), SRMA in remission (n = 4), bacterial encephalitis (n = 3), meningioma with neutrophilic inflammation (n = 4), healthy dogs (n = 6). NET-formation was detectable with IF-staining in n = 3/5 CSF samples of dogs with acute SRMA but were not detectable during remission. Vesicular NET-formation was detectable in one exemplary dog using TEM. DNase-activity was significantly reduced in dogs suffering from acute SRMA compared to healthy control group (p < 0.0001). There were no statistical differences of H3Cit levels in CSF or serum samples of acute diseased dogs compared to dogs under treatment, dogs suffering from meningioma or bacterial encephalitis or the healthy control group. Our findings demonstrate that NET-formation and insufficient NET-clearance possibly drive the immunologic dysregulation and complement the pathogenesis of SRMA. The detection of NETs in SRMA offers many possibilities to explore the aetiopathogenetic influence of this defence mechanism of the innate immune system in infectious and non-infectious canine neuropathies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wohlsein 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.)

Introduction: After being diagnosed with dementia, patients need a medical professional to empathetically address their fears and get initial questions answered. This scoping review therefore addresses how patients newly diagnosed with dementia are cared for in the general practitioner (GP) setting and how the communication between different healthcare professionals and the GP is handled., Methods: The scoping review was conducted based on the PRISMA Extension for Scoping Reviews checklist. After developing a search algorithm, literature searches were performed in PubMed, Scopus, Web of Science, Cochrane Library, PsychInfo, GeroLit and Cinahl using defined search criteria, such as a focus on qualitative study designs. After the removal of duplicates, title/abstract and full text screening was carried out., Results: Final data extraction included 10 articles out of 12,633 records. Strategies regarding the post-acute care of newly diagnosed patients included providing clarity and comfort to the patients and giving support and information both pre- and post-diagnosis. Care efforts were focused on advanced care planning and deprescribing. Involving people with dementia and their caregivers in further care was seen as crucial to provide them with the support needed. GPs emphasised the importance of listening to concerns, as well as ensuring wishes are respected, and autonomy is maintained. All studies found communication between the GP setting and other healthcare professionals regarding post-acute care to be inadequate. Lack of information sharing, clinical notes and recommendations for the GP setting resulted in inefficient provision of support, as GPs feel limited in their ability to act., Discussion: Sharing necessary information with the GP setting could promote patient-centred care for people living with dementia and facilitate appropriate and timely resource allocation and effective healthcare collaboration between the settings, for example, by defining clear care pathways and clarifying roles and expectations., (© 2024. The Author(s).)

Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3-38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function., (© 2024. The Author(s).)

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and displays vast genetic and transcriptomic heterogeneity. Current treatment guidelines recommend first-line chemoimmunotherapy consisting of an anthracycline backbone, which produces cure rates of approximately 65%. However, the remaining patients will face relapsed or refractory disease, which, even in the era of chimeric antigen receptor T cells, is difficult to treat. In this issue of Cancer Research, Marullo and colleagues investigate the biological underpinnings of the tumor-suppressive activity of the newly approved XPO1 inhibitor selinexor in the treatment of lymphoma. In a translational effort covering genomic and biochemical approaches, combined with in vivo validation experiments and a phase I clinical trial, they demonstrate that upon DNA damage, XPO1 selectively exports transcripts encoding proteins involved in genome maintenance via the RNA-binding proteins THOC4 and eIF4E. Pharmacologic interception of this export process enhances chemosensitivity in various lymphoma models, and combined selinexor plus chemoimmunotherapy displays a favorable toxicity profile and early evidence of efficacy in patients. See related article by Marullo et al., p. 101., (©2023 American Association for Cancer Research.)

Excessive and incorrect use of antibiotics contributes to the rise of antimicrobial resistance (AMR). Given that pharmacists act as final checkpoint before antibiotics is handled over to patients, they play a crucial role in promoting proper antibiotic use and ensuring treatment adherence. However, there is often a gap between the patients' needs and perceptions, and what the pharmacists provide. Improving pharmacists' training is essential for enhancing patient-centered care. The aim of this research was to evaluate the suitability of academic detailing (AD) for improving Norwegian pharmacists' knowledge and practice on adherence promoting counseling of antibiotic patients. Key insights from prior qualitative research regarding community pharmacists' position in promoting optimized antibiotic use were incorporated in a tailored AD program. The AD's suitability was evaluated using the validated "Provider Satisfaction with Academic Detailing" (PSAD) and "Detailer Assessment of Visit Effectiveness" (DAVE) instruments. Additionally, participants preferred knowledge updates method were assessed. Eighty-one of 86 visits completed PSAD (94% response rate). Satisfaction summary score for PSAD was 40.03 (of maximum 45) and scale summary score for DAVE 12.45 (of maximum 15). One-sample t -test (P < .001) indicated preference for AD over other knowledge update methods. This study confirmed that AD is a successful knowledge updating tool for improving adherence promoting counseling among Norwegian pharmacists. Future research should align practice change intentions with actions post-AD and evaluate patient impact., 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.

Delirium is common in hospitalised patients, and there is currently no specific treatment. Identifying and treating underlying somatic causes of delirium is the first priority once delirium is diagnosed. Several international guidelines provide clinicians with an evidence-based approach to screening, diagnosis and symptomatic treatment. However, current guidelines do not offer a structured approach to identification of underlying causes. A panel of 37 internationally recognised delirium experts from diverse medical backgrounds worked together in a modified Delphi approach via an online platform. Consensus was reached after five voting rounds. The final product of this project is a set of three delirium management algorithms (the Delirium Delphi Algorithms), one for ward patients, one for patients after cardiac surgery and one for patients in the intensive care unit., Competing Interests: DISCLOSURES The authors have no conflicts of interest to disclose.

Background: Current infectious disease screening recommendations for hidradenitis suppurativa (HS) are adopted from recommendations in chronic plaque psoriasis. No HS-specific guidelines for infectious disease screening prior to immunomodulatory therapy have been developed., Objectives: The aim of the study was to establish an expert Delphi consensus of recommendations regarding infectious disease screening prior to systemic immunomodulatory therapy in HS., Methods: Participants were identified via recent publications in the field and were sent a questionnaire regarding infectious diseases encountered in the setting of HS, and opinions regarding infectious disease screening prior to various systemic immunomodulatory therapies. All questions were informed by a systematic literature review regarding infections exacerbated or precipitated by immunomodulatory therapy. Questionnaire responses were followed by round-table discussion with a core group of 8 experts followed by a final round of questionnaires resulting in achievement of consensus., Results: 44 expert HS physicians from 12 countries on 5 continents participated in the development of the expert consensus recommendations. Consensus recommendations include screening for hepatitis B, hepatitis C and tuberculosis in all individuals with HS prior to therapy. All immunomodulatory therapies (biologic and systemic immunosuppressant therapy) should be preceded by infectious disease screening including patient and location-specific considerations for endemic local diseases and high-risk activities and occupations. Clinical assessment has a significant role in determining the need for laboratory screening in the setting of many uncommon or tropical diseases such as leprosy, leishmaniasis and strongyloidiasis., Conclusions: The presented consensus recommendations are the first specifically developed for pre-treatment infectious disease screening in HS., (© 2023 S. Karger AG, Basel.)

Objectives: Resource planning is a crucial component in hospitals, particularly in radiology departments. Since weather conditions are often described to correlate with emergency room visits, we aimed to forecast the amount of polytrauma-CTs using weather information., Design: All polytrauma-CTs between 01/01/2011 and 12/31/2022 (n = 6638) were retrieved from the radiology information system. Local weather data was downloaded from meteoblue.com. The data was normalized and smoothened. Daily polytrauma-CT occurrence was stratified into below median and above median number of daily polytrauma-CTs. Logistic regression and machine learning algorithms (neural network, random forest classifier, support vector machine, gradient boosting classifier) were employed as prediction models. Data from 2012 to 2020 was used for training, data from 2021 to 2022 for validation., Results: More polytrauma-CTs were acquired in summer compared with winter months, demonstrating a seasonal change (median: 2.35; IQR 1.60-3.22 vs. 2.08; IQR 1.36-3.03; p <.001). Temperature (r s  = 0.45), sunshine duration (r s  = 0.38) and ultraviolet light amount (r s  = 0.37) correlated positively, wind velocity (r s  = -0.57) and cloudiness (r s  = -0.28) correlated negatively with polytrauma-CT occurrence (all p <.001). The logistic regression model for identification of days with above median number of polytrauma-CTs achieved an accuracy of 87 % on training data from 2011 to 2020. When forecasting the years 2021-2022 an accuracy of 65 % was achieved. A neural network and a support vector machine both achieved a validation accuracy of 72 %, whereas all classifiers regarded wind velocity and ultraviolet light amount as the most important parameters., Conclusion: It is possible to forecast above or below median daily number of polytrauma-CTs using weather data., Clincical Relevance Statement: Prediction of polytrauma-CT examination volumes may be used to improve resource planning., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: To systematically review and report the rate of exudative progression over time in patients with nonexudative macular neovascularization (MNV) in age-related macular degeneration (AMD)., Design: Systematic review with prevalence meta-analyses and individual participant meta-analysis., Methods: We searched 10 literature databases on March 26, 2023, for studies of consecutive patients with treatment-naïve nonexudative MNV in AMD. The primary outcome of interest was time from diagnosis to exudative progression. We conducted meta-analyses on the prevalence of exudative progression at 1 and 2 years. Where possible, we extracted individual participant data from studies and conducted an individual participant meta-analysis and explored the exudative progression using a time-to-event curve., Results: We identified 16 eligible studies with a total of 384 eyes with nonexudative MNV. Exudative progression had occurred in 20.9% (95% CI 13.1%-29.8%) of eyes at 1 year and in 30.7% (95% CI 21.8%-40.4%) at 2 years. Similar results were observed in the individual participant meta-analysis, showing exudative progression in 18.9% (95% CI 13.5%-26.3%) of eyes at 1 year and 31.3% (95% CI 24.2%-40.0%) at 2 years. Risk factors for a fast exudative progression were the presence of subretinal lipid globules, large MNV areas, rapid MNV growth, growth in pigment epithelium detachment height and width, appearance of a branching pattern, and development of a hyporeflective halo around the MNV., Conclusions: Nonexudative MNVs in AMD are at high risk of exudative progression. Recognition of these lesions may allow for better individualized follow-up regimens in which closer monitoring may facilitate earlier diagnosis of exudative progression., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In the past decade, European animal farming has increasingly used autogenous vaccines for the prevention of nonnotifiable diseases. In Europe, these vaccines are exclusively inactivated bacterial and viral vaccines, with a set of specific regulations that differentiate them from conventional vaccines. The highest number of applications most likely occurs in poultry, as these animal species are farmed in the highest numbers compared with other types of food-producing animals. In 2019, autogenous vaccines came within the scope of harmonized European regulation for the first time, although many important aspects are still missing and need to be further developed. Consequently, several important legal provisions remain in national legislations and can vary tremendously between different member states of the European Union. The inclusion of autogenous vaccines in the management of certain diseases of poultry is justified by the nonavailability of licensed vaccines and the evolution and diversity of antigens in the field that are not covered by licensed vaccines. In addition, these vaccines aid in reducing the use of antibiotics. The methods for isolating and typing pathogenic isolates to obtain relevant antigens are pathogen specific and require a careful approach based on clinical evidence. Manufacturing processes are optimized according to regulatory standards, and they represent the most critical factor influencing the quality of autogenous vaccines and their placement on the market. This review presents the important requirements for manufacturing autogenous vaccines for poultry in addition to the relevant regulatory considerations. The results from a survey of several European Union member states regarding specific provisions within their national legislations are also presented.

Background: Two thirds of Out-of-Hospital Cardiac Arrests (OHCAs) occur at the patient's home ('at-home-CA'), where bystander CPR (B-CPR) rates are significantly lower than in public locations. Knowledge about the circumstances of this specific setting has mainly been limited to quantitative data. To develop a more conceptual understanding of the circumstances and dynamics of 'at-home CA', we conducted a qualitative interview study., Methods: Twenty-one semi-structured in-depth interviews were performed with laypersons who had witnessed 'at-home CA'. The interviews were audio recorded, transcribed, and analysed by qualitative content analysis (QCA). A category system was developed to classify facilitating and impeding factors and to finally derive overarching concepts of 'at-home CA'., Results: Qualitative Content Analysis yielded 1'347 relevant interview segments. Of these, 398 related to factors facilitating B-CPR, 328 to factors impeding, and 621 were classified neutral. Some of these factors were specific to 'at-home CA'. The privacy context was found to be a particularly supportive factor, as it enhanced the commitment to act and facilitated the detection of symptoms. Impeding factors, aggravated in 'at-home CA' settings, included limited support from other bystanders, acute stress response and impaired situational judgement, as well as physical challenges when positioning the patient. We derived six overarching concepts defining the 'at-home CA' situation: (a) unexpectedness of the event, (b) acute stress response, (c) situational judgement, (d) awareness of the necessity to perform B-CPR, (e) initial position of the patient, (f) automaticity of actions., Conclusion: Integrating these concepts into dispatch protocols and layperson training may improve dispatcher-bystander interaction and the outcomes of 'at-home CA'., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JB is an emeritus member of the ILCOR EIT (Education Implementation and Teams) Task Force. For all other authors, there is no conflict to declare., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

This study investigated the potential role of the mouse homolog of bombesin receptor-activated protein (BRAP) in imiquimod (IMQ) induced psoriasis - like skin inflammation. The expression of both human BRAP, encoded by C6orf89 , and its mouse homolog, encoded by BC004004 , has been found to be expressed abundantly in the keratinocytes. BC004004 knockout mice ( BC004004 -/- ) were topically treated with IMQ daily for 7 days to test whether they were more vulnerable to psoriasis - like inflammation. We found that those mice exhibited an altered pattern of inflammation process compared to isogenic wild type control mice ( BC004004 +/+ ). BC004004 -/- mice developed skin lesions with earlier and more acute onset, as well as a quicker remission. The cytokines related to pathogenesis of psoriasis also exhibited different expression patterns in IMQ treated BC004004 -/- mice. On day 4 of IMQ treatment, BC004004 -/- mice exhibited a higher expression level of IL-17A compared to BC004004 +/+ mice, suggesting a more robust activation of Th17 cells in the knockout mice. The serum level of thymic stromal lymphopoietin (TSLP), one of the keratinocyte derived cytokines, was also increased in BC004004 -/- mice and reached its peak on day 4. Knockdown of BRAP in cultured human keratinocyte-derived HaCaT cells by siRNA silencing led to increased release of TSLP. Our data suggest that the elevated of level of TSLP released from keratinocytes due to BRAP deficiency might mediate the crosstalk between the epidermal cells and immune cells and thereby contributing to the altered pathological changes observed in psoriasis - like skin lesion in knockout mice., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: The GMMG-CONCEPT trial investigated isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in transplant-eligible (TE) and transplant-noneligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) with exclusively high-risk disease for whom prospective trials are limited, aiming to induce minimal residual disease (MRD) negativity., Methods: This academic, investigator-initiated, multicenter, phase II trial enrolled patients with high-risk NDMM (HRNDMM) defined by mandatory International Staging System stage II/III combined with del17p, t(4;14), t(14;16), or more than three 1q21 copies as high-risk cytogenetic aberrations (HRCAs). Patients received Isa-KRd induction/consolidation and Isa-KR maintenance. TE patients received high-dose melphalan. TNE patients received two additional Isa-KRd cycles postinduction. This prespecified interim analysis (IA) reports the primary end point, MRD negativity (<10 -5 , next-generation flow), at the end of consolidation. The secondary end point was progression-free survival (PFS)., Results: Among 125 patients with HRNDMM (TE-intention-to-treat [ITT]-IA, 99; TNE-ITT, 26) of the IA population for the primary end point, the median age was 58 (TE-ITT-IA) and 74 (TNE-ITT) years. Del17p was the most common HRCA (TE, 44.4%; TNE, 42.3%); about one third of evaluable TE/TNE patients presented two or more HRCAs, respectively. The trial met its primary end point with MRD negativity rates after consolidation of 67.7% (TE) and 54.2% (TNE) of patients. Eighty-one of 99 TE-ITT-IA patients reached MRD negativity at any time point (81.8%). MRD negativity was sustained for ≥1 year in 62.6% of patients. With a median follow-up of 44 (TE) and 33 (TNE) months, median PFS was not reached in either arm., Conclusion: Isa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status, translating into a median PFS that was not yet reached after 44/33 months.

Objective: This rapid review aims to identify the types of technologies used by people with dementia and their supporters during the COVID-19 pandemic, and the issues which influenced technology adoption within their usual care routines., Methods: PubMed, PsychInfo, Scopus, and Cochrane COVID reviews were searched to identify peer-review studies published since 2020. A total of 18 studies were included and synthesised thematically., Results: Of these, most were conducted in the community ( n  = 15) with people with dementia only ( n  = 11) and involved qualitative methods ( n  = 11). The majority ( n  = 12) focused on digital off-the-shelf and low-cost solutions, such as free video conferencing platforms, to access care, socialise or take part in interventions. Whilst often well-accepted and associated with positive outcomes (such as improved social connectedness), lack of digital literacy or support to use technologies, limited access to appropriate technology, individuals' physical, cognitive, or sensory difficulties, were highlighted and likely to threaten the adoption of these solutions. The quality of the evidence was mixed, neither very robust nor easily generalisable which may be attributed to the challenges of conducting research during the pandemic or the need to rapidly adapt to a new reality., Conclusion: While COVID-19 has fast-tracked the adoption of technology, its use is likely to continue beyond the pandemic. We need to ensure this technology can leverage dementia support and care and that people with dementia are enabled and empowered to use it.

Objective: to prospectively assess sleep and sleep disorders during pregnancy and postpartum in a large cohort of women., Methods: multicenter prospective Life-ON study, recruiting consecutive pregnant women at a gestational age between 10 and 15 weeks, from the local gynecological departments. The study included home polysomnography performed between the 23rd and 25th week of pregnancy and sleep-related questionnaires at 9 points in time during pregnancy and 6 months postpartum., Results: 439 pregnant women (mean age 33.7 ± 4.2 yrs) were enrolled. Poor quality of sleep was reported by 34% of women in the first trimester of pregnancy, by 46% of women in the third trimester, and by as many as 71% of women in the first month after delivery. A similar trend was seen for insomnia. Excessive daytime sleepiness peaked in the first trimester (30% of women), and decreased in the third trimester, to 22% of women. Prevalence of restless legs syndrome was 25%, with a peak in the third trimester of pregnancy. Polysomnographic data, available for 353 women, revealed that 24% of women slept less than 6 h, and 30.6% of women had a sleep efficiency below 80%. Sleep-disordered breathing (RDI≥5) had a prevalence of 4.2% and correlated positively with BMI., Conclusions: The Life-ON study provides the largest polysomnographic dataset coupled with longitudinal subjective assessments of sleep quality in pregnant women to date. Sleep disorders are highly frequent and distributed differently during pregnancy and postpartum. Routine assessment of sleep disturbances in the perinatal period is necessary to improve early detection and clinical management., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Accurate biomarkers for disease activity and progression in patients with inflammatory bowel disease (IBD) are a prerequisite for individual disease characterization and personalized therapy. We show that metabolic profiling of serum from IBD patients is a promising approach to establish biomarkers. The aim of this work was to characterize metabolomic and lipidomic serum profiles of IBD patients in order to identify metabolic fingerprints unique to the disease., Methods: Serum samples were obtained from 55 patients with Crohn's disease (CD), 34 patients with ulcerative colitis (UC), and 40 healthy control (HC) individuals and analyzed using proton nuclear magnetic resonance spectroscopy. Classification of patients and HC individuals was achieved by orthogonal partial least squares discriminant analysis and univariate analysis approaches. Disease activity was assessed using the Gastrointestinal Symptom Rating Scale., Results: Serum metabolome significantly differed between CD patients, UC patients, and HC individuals. The metabolomic differences of UC and CD patients compared with HC individuals were more pronounced than the differences between UC and CD patients. Differences in serum levels of pyruvic acid, histidine, and the branched-chain amino acids leucine and valine were detected. The size of low-density lipoprotein particles shifted from large to small dense particles in patients with CD. Of note, apolipoprotein A1 and A2 serum levels were decreased in CD and UC patients with higher fecal calprotectin levels. The Gastrointestinal Symptom Rating Scale is negatively associated with the concentration of apolipoprotein A2., Conclusions: Metabolomic assessment of serum samples facilitated the differentiation of IBD patients and HC individuals. These differences were constituted by changes in amino acid and lipoprotein levels. Furthermore, disease activity in IBD patients was associated with decreased levels of the atheroprotective apolipoproteins A1 and A2., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Abstract: Growth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)-directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Artificial intelligence (AI), conceived in the 1950s, has permeated numerous industries, intensifying in tandem with advancements in computing power. Despite the widespread adoption of AI, its integration into medicine trails other sectors. However, medical AI research has experienced substantial growth, attracting considerable attention from researchers and practitioners., Objective: In the absence of an existing framework, this study aims to outline the current landscape of medical AI research and provide insights into its future developments by examining all AI-related studies within PubMed over the past 2 decades. We also propose potential data acquisition and analysis methods, developed using Python (version 3.11) and to be executed in Spyder IDE (version 5.4.3), for future analogous research., Methods: Our dual-pronged approach involved (1) retrieving publication metadata related to AI from PubMed (spanning 2000-2022) via Python, including titles, abstracts, authors, journals, country, and publishing years, followed by keyword frequency analysis and (2) classifying relevant topics using latent Dirichlet allocation, an unsupervised machine learning approach, and defining the research scope of AI in medicine. In the absence of a universal medical AI taxonomy, we used an AI dictionary based on the European Commission Joint Research Centre AI Watch report, which emphasizes 8 domains: reasoning, planning, learning, perception, communication, integration and interaction, service, and AI ethics and philosophy., Results: From 2000 to 2022, a comprehensive analysis of 307,701 AI-related publications from PubMed highlighted a 36-fold increase. The United States emerged as a clear frontrunner, producing 68,502 of these articles. Despite its substantial contribution in terms of volume, China lagged in terms of citation impact. Diving into specific AI domains, as the Joint Research Centre AI Watch report categorized, the learning domain emerged dominant. Our classification analysis meticulously traced the nuanced research trajectories across each domain, revealing the multifaceted and evolving nature of AI's application in the realm of medicine., Conclusions: The research topics have evolved as the volume of AI studies increases annually. Machine learning remains central to medical AI research, with deep learning expected to maintain its fundamental role. Empowered by predictive algorithms, pattern recognition, and imaging analysis capabilities, the future of AI research in medicine is anticipated to concentrate on medical diagnosis, robotic intervention, and disease management. Our topic modeling outcomes provide a clear insight into the focus of AI research in medicine over the past decades and lay the groundwork for predicting future directions. The domains that have attracted considerable research attention, primarily the learning domain, will continue to shape the trajectory of AI in medicine. Given the observed growing interest, the domain of AI ethics and philosophy also stands out as a prospective area of increased focus., (©Jin Shi, David Bendig, Horst Christian Vollmar, Peter Rasche. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 08.12.2023.)

Diffuse large B cell lymphoma (DLBCL) is a genetically highly heterogeneous disease. Yet, to date, the vast majority of patients receive standardized frontline chemo-immune-therapy consisting of an anthracycline backbone. Using these regimens, approximately 65% of patients can be cured, whereas the remaining 35% of patients will face relapsed or refractory disease, which, even in the era of CAR-T cells, is difficult to treat. To systematically tackle this high medical need, it is important to design, generate and deploy suitable in vivo model systems that capture disease biology, heterogeneity and drug response. Recently published, large comprehensive genomic characterization studies, which defined molecular sub-groups of DLBCL, provide an ideal framework for the generation of autochthonous mouse models, as well as an ideal benchmark for cell line-derived or patient-derived mouse models of DLBCL. Here we discuss the current state of the art in the field of mouse modelling of human DLBCL, with a particular focus on disease biology and genetically defined molecular vulnerabilities, as well as potential targeting strategies., Competing Interests: HCR received consulting and lecture fees from Roche, Novartis, BMS, Abbvie, AstraZeneca, Vertex and Merck; H. received research funding from Gilead Sciences and AstraZeneca. HCR is a co-founder of CDL Therapeutics GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Tabatabai, Arora, Höfmann, Jauch, von Tresckow, Hansen, Flümann, Jachimowicz, Klein, Reinhardt and Knittel.)

Biomarkers to identify metastatic breast cancer (mBC) patients resistant to CDK4/6 inhibition (CDK4/6i) are currently missing. We evaluated the usefulness of the monocyte-to-lymphocyte ratio (MLR), the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) as predictive markers for de novo resistance to CDK4/6i. Various blood cell counts and MLR, NLR, PLR were recorded before treatment initiation (baseline) and four weeks later from 97 mBC patients receiving endocrine therapy (ET) alone or in combination with CDK4/6i. Binary blood cell count/ratios (mean = cut-off) were related to outcome using Cox regression. High MLR (p = 0.001) and high NLR (p = 0.01) at baseline significantly correlated with a shorter progression-free survival (PFS) in the CDK4/6i cohort, independent of any other clinical parameter as determined by multivariate Cox regression. Both, high MLR (p = 0.008) and high NLR (p = 0.043) as well as a decrease in PLR after four weeks of CDK4/6i first line treatment (p = 0.01) indicated a shorter overall survival. Moreover, decreasing PLR (p = 0.043) and increasing mean corpuscular volume (MCV; p = 0.011) within the first cycle of CDK4/6i correlated with a shorter PFS and decreasing MLR (p = 0.039) within the first cycle of first-line CDK4/6i was also correlated with shorter PFS. In summary, easily assessable blood cell parameter were shown to have predictive, monitoring and prognostic value and thus, could, in future, be used for individualized CDK4/6i therapy management. Most importantly, the imbalance of NLR and MLR at baseline might serve as predictive marker for de novo resistance to CDK4/6i in mBC patients., (© 2023. The Author(s).)

This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human DC from lymphoid organs, and various non-lymphoid tissues. Within this chapter, detailed protocols are presented that allow for the generation of single-cell suspensions from mouse lymphohematopoietic tissues including spleen, peripheral lymph nodes, and thymus, with a focus on the subsequent analysis of DC by flow cytometry. However, prepared single-cell suspensions can be subjected to other applications including sorting and cellular enrichment procedures, RNA sequencing, Western blotting, and many more. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists., (© 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Objectives: The treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) changed remarkably since the European Medicines Agency-approved chimeric antigen receptor T-cell (CAR-T) therapies (axicabtagene ciloleucel [axi-cel], lisocabtagene maraleucel [liso-cel], tisagenlecleucel [tisa-cel]) for the third-line onwards (3+L), and targeted therapies (polatuzumab vedotin-bendamustine-rituximab [pola-BR], tafasitamab-lenalidomide [Tafa-L]) for the second-line (2L) onwards. As associated rising treatment costs represent an economic burden, the cost-effectiveness of transplant-ineligible R/R DLBCL interventions was assessed from a German healthcare payer's perspective, using the efficiency frontier (EF) approach., Methods: A systematic literature review was performed to determine the clinical benefit concerning median overall survival (OS) of bendamustine-rituximab (BR), rituximab-gemcitabine-oxaliplatin (R-GemOx), axi-cel, liso-cel, tisa-cel, pola-BR, and Tafa-L. First-year treatment costs (drug and medical services costs) were calculated. Results were merged on two-dimensional graphs illustrating 2L and 3+L EFs., Results: Second-line EF is formed by BR (median OS 11.49 months, €23 958) and Tafa-L (45.7, €104 541), 3+L EF is formed by R-GemOx (12.0, €29 080), Tafa-L (15.5, €104 541), and axi-cel (18.69, €308 516). These interventions build the respective cost-effectiveness thresholds for novel interventions., Conclusions: Using the EF approach, the currently most cost-effective interventions (based on cost-effectiveness ratios) in the indication of R/R DLBCL were identified to guide international reimbursement decisions., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Unique data is reported on the transfer of 129 I iodine from freshwaters to fish as well as the internal distribution within fish from the Fukushima and Chernobyl exclusion zones (ChEZ). Samples of water, sediments and fish were collected in the contaminated ponds Inkyozaka and Suzuuchi, and in the less contaminated Abukuma river in Fukushima, as well as in the contaminated Glubokoye lake and in the less contaminated Starukha lake in ChEZ. In water, 129 I was mainly present as low molecular mass (LMM) and negatively charged species, while a minor fraction was associated with colloidal fraction, most probably organic material in water. The sediment-water 129 I apparent distribution coefficients, Kd, ranged from 225 to 329 L/kg, equal that of stable iodine, but did not correlate with 129 I/ 127 I ratio or 129 I/ 137 Cs ratio as the environmental distribution of radioactive iodine was different from that of stable iodine and radioactive cesium. Concentration ratios (CR) of 129 I in muscle of freshwater fish ranged from 85 to 544 across waterbodies with limited water exchange, similar in Fukushima and Chernobyl, but varied with respect to fish species. Thus, this is the first results on the transfer of 129 I to freshwater fish, showing that the CR for freshwater fish is higher than CR reported for marine fish. Concentrations of 129 I in fish muscle were, however, lower than in the intestinal content, indicating the influence of more contaminated dietary ingredients probably of terrestrial origin based due to δ 13 C signal on as well as of biodilution. The present results highlighted also that the radiation dose in fish was highly inhomogeneously distributed. Based on the present 129 I/ 127 I atomic ratio of 10 -5 in the most contaminated fish in the ponds in Fukushima and Glubokoye lake in Chernobyl, however, a radiation dose of 10 μSv/y would not pose any harm to the fish population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

While it is often assumed that liquid-vapor interfaces in nonequilibrium processes are in states of local thermodynamic equilibrium, this might not be the case for strong deviations from equilibrium. Clausius-Clapeyron equations for bulk properties yield a consistently defined temperature of the interface that is close to the liquid bulk temperature. The alternative interface temperature defined through the surface tension will be different for stronger nonequilibrium processes. Structural variables are introduced to extend the thermodynamic description of interfaces to a wider range of processes. Interfacial resistivities will depend on interface temperature as well as mass and heat flux through the interface.

Some people react abnormally when exposed to sunlight by getting easily burned or develop a rash. When testing a patient's level of photosensitivity in the clinic, the UVR dose to provoke erythema is determined by the minimal erythema dose (MED) test. Subsequently, a photoprovocation test is performed to detect abnormal skin reactions by daily exposing the skin to UVR for several consecutive days. Associated problems in MED testing include choice of an even skin area for testing, patients keeping still during the test, testing with different UVR doses simultaneously, and securing clear borders of erythema. To address these issues, a MED Test Patch was developed which adheres closely to the skin to ensure sharp erythema borders and provides six irradiation fields with decremental doses of 20%. For MED testing, we constructed a solar simulator and LED lamps with peak emissions at 309 and 370 nm, small enough to be mounted directly on to the MED Test Patch and accommodate patient movements. These lamps and a 415 nm LED can also be used for provocation testing which is best performed on the back where the skin is assumed to have identical UVR sensitivity, and the area is large enough for adjacent MED and provocation test fields. Reading of erythema is still performed by visual and tactile evaluation. The UVA and UVB MED test can be performed in 1 h. The advantage of these developments is an easy-to-use, standardized test method with improved accuracy of the results., (© 2023. The Author(s).)

Purpose: Identification of patients at risk of complicated or more severe COVID-19 is of pivotal importance, since these patients might require monitoring, antiviral treatment, and hospitalization. In this study, we prospectively evaluated the SACOV-19 score for its ability to predict complicated or more severe COVID-19., Methods: In this prospective multicenter study, we included 124 adult patients with acute COVID-19 in three German hospitals, who were diagnosed in an early, uncomplicated stage of COVID-19 within 72 h of inclusion. We determined the SACOV-19 score at baseline and performed a follow-up at 30 days., Results: The SACOV-19 score's AUC was 0.816. At a cutoff of > 3, it predicted deterioration to complicated or more severe COVID-19 with a sensitivity of 94% and a specificity of 55%. It performed significantly better in predicting complicated COVID-19 than the random tree-based SACOV-19 predictive model, the CURB-65, 4C mortality, or qCSI scores., Conclusion: The SACOV-19 score is a feasible tool to aid decision making in acute COVID-19., (© 2023. The Author(s).)

Until recently, studying the murine methylome was restricted to sequencing-based methods. In this study we compared the global DNA methylation levels of hairless mouse epidermis using the recently released Infinium Mouse Methylation BeadChip from Illumina and whole genome bisulphite sequencing (WGBS). We also studied the effect of sample storage conditions by using fresh and fresh-frozen epidermis. The DNA methylation levels of 123,851 CpG sites covered by both the BeadChip and WGBS were compared. DNA methylation levels obtained with WGBS and the BeadChip were strongly correlated (Pearson correlation r = 0.984). We applied a threshold of 15 reads for the WGBS methylation analysis. Even at a threshold of 10 reads, we observed no substantial difference in DNA methylation levels compared with that obtained with the BeadChip. The DNA methylation levels from the fresh and the fresh-frozen samples were strongly correlated when analysed with both the BeadChip (r = 0.999) and WGBS (r = 0.994). We conclude that the two methods of analysis generally work equally well for studies of DNA methylation of mouse epidermis and find that fresh and fresh-frozen epidermis can generally be used equally well. The choice of method will depend on the specific study's aims and the available resources in the laboratory.

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Purpose: Currently, various techniques are available to mark and selectively remove initially suspicious axillary lymph nodes (target lymph nodes, TLNs) in breast cancer patients receiving neoadjuvant chemotherapy (NACT). To date, limited data are available on whether the use of magnetic seeds (MS) is suitable for localizing TLNs. This study aimed to investigate the feasibility of MS in patients undergoing target lymph node biopsy (TLNB) or targeted axillary dissection (TAD) after NACT., Methods: Prospective data from the ongoing multicentric AXSANA study were extracted from selected patients in whom the TLN had been marked with an MS before NACT and who were enrolled from June 2020 to June 2023. The endpoints of the analysis were the detection rate, the rate of lost markers, and the potential impairment on magnetic resonance imaging (MRI) assessment., Results: In 187 patients from 27 study sites in seven countries, MS were placed into the TLN before NACT. In 151 of these, post-NACT surgery had been completed at the time of analysis. In 146 patients (96.0%), a TLN could successfully be detected. In three patients, the seed was removed but no lymphoid tissue was detected on histopathology. The rate of lost markers was 1.2% (2 out of 164 MS). In 15 out of 151 patients (9.9%), MRI assessment was reported to be compromised by MS placement., Conclusion: MS show excellent applicability for TLNB/TAD when inserted before NACT with a high DR and a low rate of lost markers. Axillary MS can impair MRI assessment of the breast., Trial Registration Number: NCT04373655 (date of registration May 4, 2020)., (© 2023. The Author(s).)

The objective of this pilot study was to assess the impact of a salivary gland ultrasound (SGUS) atlas for scoring parenchymal changes in Sjögren's syndrome by assessing the reliability of the scoring system (0-3), without and with the use of the SGUS atlas. Ten participants with varying experience in SGUS contributed to the reliability exercise. Thirty SGUS images of the submandibular and parotid gland with abnormalities ranging from 0 to 3 were scored using the written definitions of the OMERACT SGUS scoring system and using the SGUS atlas based on the OMERACT scoring system. For intra-reader reliability, two rounds were performed without and with the atlas-in the 2nd round the 30 images were rearranged in random order by a physician not included in the scoring. Inter-reader reliability was also determined in both rounds. Without using the atlas, the SGUS OMERACT scoring system showed fair inter-reader reliability in round 1 (mean kappa 0.36; range 0.06-0.69) and moderate intra-reader reliability (mean kappa 0.55; range 0.28-0.81). With the atlas, inter-reader reliability improved in round 1 to moderate (mean kappa 0.52; range 0.31-0.77) and intra-reader reliability to good (mean kappa 0.69; range 0.46-0.86). Higher intra-reader reliability was noted in participants with previous SGUS experience. The SGUS atlas increased both intra- and inter-reader reliability for scoring gland pathology in participants with varying SGUS experience suggesting a possible future role in clinical practice and trials. Key Points • Ultrasonography can detect parenchymal changes in salivary glands in patients with Sjögren's disease. • An ultrasound atlas may improve reliability of scoring parenchymal changes in salivary glands., (© 2023. The Author(s).)

Despite advances in allogeneic hematopoietic cell transplantation, acute graft-versus-host disease (aGVHD) remains its leading complication, yet with heterogeneous outcomes. Here, we analyzed aGVHD phenotypes and clinical classifications in depth in large, multicenter cohorts involving 3019 patients and addressed prevailing gaps by developing data-driven models. We compared, tested and verified these along with all conventional classifications in independent cohorts and found that data-driven grading outperformed conventional grading in Akaike information criterion and concordance index metrics. Data-driven classifications refined aGVHD assessment with up to 12 severity grades, which were associated with distinct nonrelapse mortality (NRM) and confirmed the key role of intestinal aGVHD. We developed an online calculator for physicians to implement principal component-derived grading (PC1). These results provide substantial insight into the evaluation of aGVHD phenotypes and multiorgan involvement, which relegates the exclusive reporting of overall aGVHD severity grades in transplant registries and clinical trials. Data-driven aGVHD grading provides an expandable platform to refine classification and transplant risk assessment., (© 2023. The Author(s).)

Polymer concrete has proved to be advantageous in machine building for many years thanks to its excellent damping properties. Until now, its use was limited to machine beds due to its comparatively low tensile strength. Its use in moving structural components has not been possible until now. Recent research results have shown that this challenge can be met by integrating prestressed carbon fibers. Until now, the production of samples out of prestressed fiber-reinforced polymer concrete has been carried out according to fixed specifications. It is not yet clear whether these specifications are suitable to fully exploit the potential of the material. Samples manufactured to these specifications show at least a large scatter in bending stiffness. Within the scope of this paper, the existing manufacturing process is validated by the variation of process steps. Specifically, this involved the use of a shaker, variation of the dwell time in the mold, variation of the resin content, and the procedure for impregnating the fibers. The characterization of the samples showed that the scatter could only be reduced by increasing the dwell time. However, this leads to a decrease in bending stiffness and, thus, is not suitable for further improvement of the novel material.

Introduction: This study aimed to investigate the epidemiology, serotype distribution, phenotypical antibiogram, and molecular resistance gene characteristics of invasive Haemophilus influenzae infections in Denmark from 2014 to 2022. Additionally, the potential impact of outdoor temperature and COVID-19 restrictions on the epidemiology of H. influenzae was assessed., Materials and Methods: Invasive H. influenzae isolates were received from patients with positive culture results from cerebrospinal fluid, blood, or other sterile sites. Sample data were obtained from the Danish laboratory surveillance system/MiBa database, and whole-genome sequencing (WGS) was performed on the isolates. The incidence rates and distribution of H. influenzae cases were analyzed, and antibiotic susceptibility were assessed., Results: A total of 1,007 invasive H. influenzae cases were identified, with serotyping conducted for 752 (74.7%) isolates. The median incidence per year of H. influenzae was 2.0 cases per 100,000, with the highest incidence in 2014 and the lowest in 2020. The majority of H. influenzae isolates were non-typeable H. influenzae (NTHi), while the most prominent serotypes were serotype f followed by serotype b. Bacteremia cases accounted for the majority (88.6%) of occurrences, although meningitis cases showed an increasing trend during the time period. The age group 85+ exhibited the highest incidence. The implementation of COVID-19 preventive interventions in 2020 resulted in a significant reduction in H. influenzae incidence, which returned to pre-COVID levels in 2021. A negative correlation was observed between monthly H. influenzae cases and outdoor temperature. An overall level of genetic beta-lactamase resistance of 26.3% was observed divided into 10.6% beta-lactamase-positive ampicillin-resistant (gBLPAR), 13.6% beta-lactamase-negative ampicillin-resistant (gBLNAR) and 2.1% beta-lactamase-positive amoxicillin clavulanate-resistant (gBLPACR). Other non-beta-lactam resistance traits were detected in 7.6% of isolates (primarily aminoglycoside-modifying enzymes)., Conclusion: The overall incidence of H. influenzae in Denmark returned to stable levels after the COVID-19 epidemic, with NTHi strains dominating. The COVID-19 preventive interventions led to a major reduction in incidence. A significant negative correlation between the incidence of H. influenzae and temperature was observed. The study revealed an overall genetic beta-lactam resistance rate of 26.3%, and the concordance between genotypic and phenotypic beta-lactam resistance was high (98.2%)., 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 © 2023 Slotved, Johannesen, Stegger, Dalby and Fuursted.)

Background: Disturbed bile acid homeostasis associated with a rise of primary and a decline of secondary bile acids is a consistent finding in inflammatory bowel diseases (IBDs). Whether fecal bile acids may emerge as biomarkers for IBD diagnosis and disease severity is less clear. Our study aimed to identify associations of 18 fecal bile acid species with IBD entity and disease activity., Methods: Stool samples of 62 IBD patients and 17 controls were collected. Eighteen fecal bile acid species were quantified by LC-MS/MS using stable isotope dilution. Lipid levels normalized to a dry weight of the fecal homogenates and ratios of single bile acid species to total bile acid levels were used for calculations., Results: IBD patients exhibited altered primary and secondary bile acid ratios in stool, with notable distinctions between ulcerative colitis (UC) compared to Crohn's disease (CD) and healthy controls. Fecal calprotectin was negatively correlated with glycolithocholic acid (GLCA) and hyodeoxycholic acid (HDCA) in UC. These bile acids were reduced in stool of UC patients with fecal calprotectin levels > 500 µg/g compared to UC patients with low calprotectin levels. Moreover, negative associations of six secondary bile acids with C-reactive protein (CRP) existed in UC. In CD patients, fecal bile acids did not correlate with CRP or fecal calprotectin. Diarrhoea is common in IBD, and UC patients with diarrhoea had reduced deoxycholic acid (DCA), glycine conjugated DCA (GDCA) and lithocholic acid in stool in contrast to patients with normal stool consistency. Fecal bile acid levels were not associated with diarrhoea in CD patients. UC patients treated with mesalazine had increased levels of fecal GDCA whereas no such changes were observed in CD patients. Bile acid levels of CD and UC patients treated with biologicals or corticosteroids did not change. Relative levels of GHDCA (specificity: 79%, sensitivity: 67%) and glycochenodeoxycholic acid (specificity: 74%, sensitivity: 63%) were the most specific to distinguish UC from CD., Conclusion: Disrupted fecal bile acid homeostasis is associated with disease severity and disease symptoms in UC but not in CD, potentially aiding in distinguishing IBD subtypes and classifying the pathophysiology of diarrhoea in UC., (© 2023. The Author(s).)

Background: Needle visualization is essential to avoid vascular puncture and nerve injury in ultrasound-guided regional anesthesia. Several factors that statistically influence needle visibility have been described but the dimensions of their individual impact remain unclear. This study aimed to quantify the impact of various independent factors on ultrasound needle visibility., Methods: A total of 1500 ultrasound videos of in-plane needle insertions were obtained in embalmed cadavers with ten different commercially available echogenic and non-echogenic needles at different insertion angles and bevel orientations in a full factorial study design. The visibility of needle tip and shaft were rated as "good" or "poor" visibility. Nominal logistic regression analyses were calculated for the visibility of the needle tip and shaft., Results: SonoPlex Stim Sprotte, SonoTAP Facet (needle tip and shaft) and Spinostar PencilPoint (needle tip)), insertion angle and bevel orientation were associated with good ultrasound visibility, reaching statistical significance (p < 0.05). The range of the effect on the log-odds scale for needle tip visibility was largest for the insertion angle with 6.33, followed by the tissue condition (3.76), bevel orientation (1.45) and the needle types (1.25). Regarding the needle shaft visibility, the largest effect range was observed with the insertion angle (7.36), followed by the tissue conditions with 3.96, needle type (1.86) and bevel orientation (0.95)., Conclusion: In-plane needle visibility in ultrasound images depends mainly on the insertion angle, as expected. This is closely followed by the tissue condition, which is a factor related to the patient, thus cannot be altered to improve needle visibility. In the dimensions of the log-odds scale, the choice of a specific needle is far less important towards achieving a good visualization, whereas optimizing the bevel orientation can have a larger impact than the needle choice. Concluding from the relative dimensions of factors that determine needle visibility in this model, the importance of needles with echogenic features may be overrated., (© 2023. The Author(s).)

Anti-NMDA receptor (NMDAR) autoantibodies cause NMDAR encephalitis, the most common autoimmune encephalitis, leading to psychosis, seizures, and autonomic dysfunction. Current treatments comprise broad immunosuppression or non-selective antibody removal. We developed NMDAR-specific chimeric autoantibody receptor (NMDAR-CAAR) T cells to selectively eliminate anti-NMDAR B cells and disease-causing autoantibodies. NMDAR-CAARs consist of an extracellular multi-subunit NMDAR autoantigen fused to intracellular 4-1BB/CD3ζ domains. NMDAR-CAAR T cells recognize a large panel of human patient-derived autoantibodies, release effector molecules, proliferate, and selectively kill antigen-specific target cell lines even in the presence of high autoantibody concentrations. In a passive transfer mouse model, NMDAR-CAAR T cells led to depletion of an anti-NMDAR B cell line and sustained reduction of autoantibody levels without notable off-target toxicity. Treatment of patients may reduce side effects, prevent relapses, and improve long-term prognosis. Our preclinical work paves the way for CAAR T cell phase I/II trials in NMDAR encephalitis and further autoantibody-mediated diseases., Competing Interests: Declaration of interests Related to this work, the German Center for Neurodegenerative Diseases (DZNE) and Max-Delbrück-Centrum Berlin have filed a patent application describing NMDAR-CAAR T cells for treatment of NMDAR encephalitis on which S.M.R., I.E., and H.P. are named as inventors (WO/2020/245343). In addition, the DZNE has filed a patent application on constructs for detection and isolation of NMDAR autoantibodies on which H.-C.K. and H.P. are named as inventors (WO/2021/008890)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: We investigated intestinal permeability and fecal, plasma, and urine metabolomic profiles in methotrexate-treated active psoriatic arthritis (PsA) and how this related to clinical response following one sham or fecal microbiota transplantation (FMT)., Methods: This exploratory study is based on the FLORA trial cohort, in which 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate-treatment, were included in a 26-week, double-blind, 1:1 randomized, sham-controlled trial. Participants were randomly allocated to receive either one healthy donor FMT (n = 15) or sham (n = 16) via gastroscopy. The primary trial end point was the proportion of treatment failures through 26 weeks. We performed a lactulose-to-mannitol ratio (LMR) test at baseline (n = 31) and at week 26 (n = 26) to assess small intestinal permeability. Metabolomic profiles in fecal, plasma, and urine samples collected at baseline, weeks 4, 12, and 26 were measured using 1 H Nuclear Magnetic Resonance., Results: Trial failures (n = 7) had significantly higher LMR compared with responders (n = 19) at week 26 (0.027 [0.017-0.33]) vs. 0.012 [0-0.064], P = 0.013), indicating increased intestinal permeability. Multivariate analysis revealed a significant model for responders (n = 19) versus failures (n = 12) at all time points based on their fecal (P < 0.0001) and plasma (P = 0.005) metabolomic profiles, whereas urine metabolomic profiles did not differ between groups (P = 1). Fecal N-acetyl glycoprotein GlycA correlated with Health Assessment Questionnaire Disability Index (coefficient = 0.50; P = 0.03) and fecal propionate correlated with American College of Rheumatology 20 response at week 26 (coefficient = 27, P = 0.02)., Conclusion: Intestinal permeability and fecal and plasma metabolomic profiles of patients with PsA were associated with the primary clinical trial end point, failure versus responder., (© 2023 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Rationale and Objectives: To assess the potential of 0.55T low-field MRI system in lumbar spine imaging with and without the use of additional advanced postprocessing techniques., Materials and Methods: The lumbar spine of 14 volunteers (32.9 ± 3.6 years) was imaged both at 0.55T and 1.5T using sequences from clinical routine. On the 0.55T scanner system, additional sequences with simultaneous multi-slice acquisition and artificial intelligence-based postprocessing techniques were acquired. Image quality of all 28 examinations was assessed by three musculoskeletal radiologists with respect to signal/contrast, resolution, and assessability of the spinal canal and neuroforamina using a 5-point Likert scale (1 = non-diagnostic to 5 = perfect quality). Interrater agreement was evaluated with the Intraclass Correlation Coefficient and the Mann-Whitney U test (significance level: p < 0.05)., Results: Image quality at 0.55T was rated lower on the 5-point Likert scale compared to 1.5T regarding signal/contrast (mean: 4.16 ± 0.29 vs. 4.54 ± 0.29; p < 0.001), resolution (4.07 ± 0.31 vs. 4.49 ± 0.30; p < 0.001), assessability of the spinal canal (4.28 ± 0.13 vs. 4.73 ± 0.26; p < 0.001) and the neuroforamina (4.14 ± 0.28 vs. 4.70 ± 0.27; p < 0.001). Image quality for the AI-processed sagittal T1 TSE and T2 TSE at 0.55T was also rated slightly lower, but still good to perfect with a concomitant reduction in measurement time. Interrater agreement was good to excellent (range: 0.60-0.91)., Conclusion: While lumbar spine image quality at 0.55T is perceived inferior to imaging at 1.5T by musculoskeletal radiologists, good overall examination quality was observed with high interrater agreement. Advanced postprocessing techniques may accelerate intrinsically longer acquisition times at 0.55T., (Copyright © 2023 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

A 78-year-old female patient sustained a left-sided proximal femoral fracture due to a fall. Since childhood the patient had suffered from ankylosis of unknown origin in the ipsilateral hip joint. The recommended intramedullary osteosynthesis could restore the original status quo before the fracture. It needs less time in the operating room (OR) and includes a lower risk for intraoperative complications than a hip joint endoprosthesis. Arthroplasty can lead to a significant improvement in mobility of the hip joint but requires more time in the OR for the surgical procedure and anesthesia time and includes a higher risk for intraoperative and postoperative complications. The antetorsion angle of 76° in this patient deviated extremely from the standard and made the intramedullary osteosynthesis for this type of fracture a challenge. Using improvised techniques led to a load-stable fracture treatment that ultimately led to a satisfactory result., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Both bombesin receptor-activated protein (BRAP) and its mouse homolog have been found to be expressed in bronchial epithelia but with unclear functions. Using electron microscopy combined with histological assays, we found that BRAP homolog deficiency in mice led to abnormal tracheal cilia. Rab-3A-interacting protein (Rabin8), a protein that might play a role in cilia development, was screened by yeast two-hybrid and further verified to have interaction with human BRAP by co-immunoprecipitation and pulldown assays. The expression levels of Rabin8, together with acetylated α-tubulin, a marker of cilia, were either downregulated by knockdown of BRAP or upregulated by overexpression of BRAP in cultured immortalized human bronchial epithelial cells. These results reveal a role for BRAP in airway cilia formation., (© 2023 Federation of European Biochemical Societies.)

For the safety and efficacy of frozen cell therapy products, determination of cellular viability is key. However, results of cell viability measurements do not only depend on the cell line or on the inflicted stress, but also on the assay used, making inter-experimental comparisons difficult. The aim of this study was thus to assess commonly used viability assays in clinically relevant human mesenchymal/stromal stem cells and human A549 lung carcinoma cells. Post freeze-thaw stress viability and proliferation were evaluated under different conditions using trypan blue, acridine orange/DAPI stain, alamarBlue, ATP, and neutral red assays. Significant differences in cell viability between metabolic assays were observed, likely due to their distinct intrinsic detection mechanisms. Membrane-integrity based assays generally overestimated cell viabilities in this study. Furthermore, noticeable differences in inter-assay sensitivities were observed. These differences highlight that cell viability methods should be meticulously selected and their associated results carefully interpreted in a relevant context to ensure reliable conclusions. Indeed, although cell membrane integrity based assays are a popular choice to determine cellular quality attributes after freezing and thawing, we demonstrate that metabolic assays may be more suitable in this context., Competing Interests: Declaration of Competing Interest This research was funded by and conducted at Lonza Ltd., Basel. M. K. was supported by a grant from Lonza, L. S. was employed at Lonza Ltd., Basel at the time of this work. HC. M. and J. H. are not affiliated with Lonza. The authors have not received any additional benefits. None of the disclosed methods or formulations are currently commercially applied and hence there is no direct financial benefit for Lonza., (Copyright © 2023 Elsevier Inc. All rights reserved.)