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The characterization of genetic alterations in tumor samples has become standard practice for many human cancers to achieve more precise disease classification and guide the selection of targeted therapies. Cerebrospinal fluid (CSF) can serve as a source of tumor DNA in patients with central nervous system (CNS) cancer. We performed comprehensive profiling of CSF circulating tumor DNA (ctDNA) in 711 patients using an FDA-authorized platform (MSK-IMPACT™) in a hospital laboratory. We identified genetic alterations in 489/922 (53.0%) CSF samples with clinically documented CNS tumors. None of 85 CSF samples from patients without CNS tumors had detectable ctDNA. The distribution of clinically actionable somatic alterations was consistent with tumor-type specific alterations across the AACR GENIE cohort. Repeated CSF ctDNA examinations from the same patients identified clonal evolution and emergence of resistance mechanisms. ctDNA detection was associated with shortened overall survival following CSF collection. Next-generation sequencing of CSF, collected through a minimally invasive lumbar puncture in a routine hospital setting, provides clinically actionable cancer genotype information in a large fraction of patients with CNS tumors., (© 2024. The Author(s).)

Introduction: There are no guidelines or prospective studies defining the optimal surgical treatment for glioblastomas in older patients (≥70 years), for those with a limited functioning performance at presentation (Karnofsky Performance Scale ≤70) or for those with tumours in certain locations (midline, multifocal). Therefore, the decision between resection and biopsy is varied, among neurosurgeons internationally and at times even within an institution. This study aims to compare the effects of maximal tumour resection versus tissue biopsy on survival, functional, neurological and quality of life outcomes in these patient subgroups. Furthermore, it evaluates which modality would maximise the potential to undergo adjuvant treatment., Methods and Analysis: This study is an international, multicentre, prospective, two-arm cohort study of an observational nature. Consecutive patients with glioblastoma will be treated with resection or biopsy and matched with a 1:1 ratio. Primary endpoints are (1) overall survival and (2) proportion of patients that have received adjuvant treatment with chemotherapy and radiotherapy. Secondary endpoints are (1) proportion of patients with National Institute of Health Stroke Scale deterioration at 6 weeks, 3 months and 6 months after surgery; (2) progression-free survival (PFS); (3) quality of life at 6 weeks, 3 months and 6 months after surgery and (4) frequency and severity of serious adverse events. The total duration of the study is 5 years. Patient inclusion is 4 years; follow-up is 1 year., Ethics and Dissemination: The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media., Trial Registration Number: NCT06146725., Competing Interests: Competing interests: None declared., (© 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.)

Photoenzymes are light-powered biocatalysts that typically rely on the excitation of cofactors or unnatural amino acids for their catalytic activities 1,2 . A notable natural example is the fatty acid photodecarboxylase (FAP), which uses light energy to convert aliphatic carboxylic acids to achiral hydrocarbons 3 . Here, we report a way to design a non-natural photodecarboxylase based on the excitation of enzyme-bound catalytic intermediates, instead of relying on cofactor excitation 4 . Iminium ions 5 , transiently generated from enals within the active site of an engineered class I aldolase 6 , can absorb violet light and function as single-electron oxidants. Activation of chiral carboxylic acids, followed by decarboxylation, generates two radicals that undergo stereospecific cross-coupling, yielding products with two stereocenters. Using the appropriate enantiopure chiral substrate, the desired diastereoisomeric product is selectively obtained with complete enantiocontrol. This finding underscores the active site's ability to transfer stereochemical information from the chiral radical precursor into the product, effectively addressing the longstanding problem of rapid racemization of chiral radicals. The resulting 'memory of chirality' scenario 7 is a rarity in enantioselective radical chemistry., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease (ILD) in sensitized individuals caused by a large variety of inhaled antigens. The clinical form of acute HP is often misdiagnosed, while the chronic form, especially the chronic fibrotic HP, is difficult to differentiate from other fibrotic ILDs. The present guideline for the diagnosis and treatment of HP replaces the former German recommendations for the diagnosis of HP from 2007 and is amended explicitly by the issue of the chronic fibrotic form, as well as by treatment recommendations for the first time. The evidence was discussed by a multidisciplinary committee of experts. Then, recommendations were formulated for twelve questions on important issues of diagnosis and treatment strategies. Recently published national and international guidelines for ILDs and HP were considered. Detailed background information on HP is useful for a deeper insight into HP and the handling of the guideline., Competing Interests: Eine Übersicht der Interessenkonflikte findet sich im Internet unter http://awmf.org; AWMF-Registriernummer 020-036., (Thieme. All rights reserved.)

Objectives: Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD., Materials and Methods: A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale., Results: Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD ( P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI ( P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups ( P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse., Conclusions: The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD., Competing Interests: Conflicts of interest and sources of funding: The authors have declared that no conflict of interest exists. This work was supported by the Deutsche Forschungsgemeinschaft (DFG German Research Foundation) through projects EXC-2047/1-390685813 and EXC2151-390873048 and by the EU–Joint Programme for Neurodegenerative Disease Research through project 01ED2208., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Random survival forests (RSF) can be applied to many time-to-event research questions and are particularly useful in situations where the relationship between the independent variables and the event of interest is rather complex. However, in many clinical settings, the occurrence of the event of interest is affected by competing events, which means that a patient can experience an outcome other than the event of interest. Neglecting the competing event (i.e., regarding competing events as censoring) will typically result in biased estimates of the cumulative incidence function (CIF). A popular approach for competing events is Fine and Gray's subdistribution hazard model, which directly estimates the CIF by fitting a single-event model defined on a subdistribution timescale. Here, we integrate concepts from the subdistribution hazard modeling approach into the RSF. We develop several imputation strategies that use weights as in a discrete-time subdistribution hazard model to impute censoring times in cases where a competing event is observed. Our simulations show that the CIF is well estimated if the imputation already takes place outside the forest on the overall dataset. Especially in settings with a low rate of the event of interest or a high censoring rate, competing events must not be neglected, that is, treated as censoring. When applied to a real-world epidemiological dataset on chronic kidney disease, the imputation approach resulted in highly plausible predictor-response relationships and CIF estimates of renal events., (© 2024 The Author(s). Biometrical Journal published by Wiley‐VCH GmbH.)

Introduction: VEXAS syndrome, characterized by a UBA1 gene mutation, is a rare and severe systemic inflammatory disease predominantly affecting men. Since its initial description in 2020, it has been noted for its broad clinical phenotype and frequent misdiagnosis., Case Presentation: A 76-year-old Caucasian male patient diagnosed with VEXAS syndrome is presented in this case report. He presented with typical symptoms including pulmonary manifestations (infiltrates and effusions), systemic inflammation, and haematological abnormalities. The diagnosis was challenging due to the disease's heterogeneous presentation, often resembling autoimmune or haematological diseases. This patient's case featured ground-glass opacities and pleural effusions, underlining the significant pulmonary involvement seen in 50-67% of VEXAS patients. His condition was further complicated by recurrent fever and systemic inflammation affecting multiple organs., Conclusion: VEXAS syndrome demands an aggressive treatment approach due to its high mortality rate and refractory nature. This case underscores the importance of including VEXAS syndrome in differential diagnoses, particularly for patients with systemic inflammation and pulmonary symptoms, and calls for multidisciplinary management and extensive research to understand its full range of clinical phenotypes., (© 2024. The Author(s).)

Purpose: To examine the in-vitro expression of matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) in corneal stromal cells by distinguishing between fibroblasts and keratocytes of healthy and keratoconus (KC) corneas., Methods: Stromal cells were isolated from healthy and KC corneas (n = 8). A normal-glucose, serum-containing cell culture medium (NGSC-medium) was used for cultivation of healthy human corneal fibroblasts (HCFs) and KC human corneal fibroblasts (KC-HCFs). In order to obtain a keratocyte phenotype, the initial cultivation with NGSC-medium was changed to a low-glucose, serum-free cell culture medium for healthy (Keratocytes) and KC cells (KC-Keratocytes). Gene and protein expression of MMP-1, -2, -3, -7, -9 and TIMP-1, -2, -3 were measured by quantitative PCR and Enzyme-Linked Immunosorbent Assay (ELISA) from the cell culture supernatant., Results: KC-HCFs demonstrated a lower mRNA gene expression for MMP-2 compared to HCFs. In contrast to their respective fibroblast groups (either HCFs or KC-HCFs), Keratocytes showed a higher mRNA gene expression of TIMP-3, whereas TIMP-1 mRNA gene expression was lower in Keratocytes and KC-Keratocytes. Protein analysis of the cell culture supernatant revealed lower concentrations of MMP-1 in KC-HCFs compared to HCFs. Compared to Keratocytes, TIMP-1 concentrations was lower in the cell culture supernatant of KC-Keratocytes. In HCFs and KC-HCFs, protein levels of MMP-1 and TIMP-1 were higher and MMP-2 was lower compared to Keratocytes and KC-Keratocytes, respectively., Conclusion: This study indicates an imbalance in MMP and TIMP expression between healthy and diseased cells. Furthermore, differences in the expression of MMPs and TIMPs exist between corneal fibroblasts and keratocytes, which could influence the specific proteolytic metabolism in-vivo and contribute to the progression of KC., (© 2024. The Author(s).)

Postoperative Delirium (POD) is the most common complication following surgery among older adults, and has been consistently associated with increased mortality and morbidity, cognitive decline, and loss of independence, as well as markedly increased health-care costs. The development of new tools to identify individuals at high risk for POD could guide clinical decision-making and enable targeted interventions to potentially decrease delirium incidence and POD-related complications. In this study, we used machine learning techniques to evaluate whether baseline (pre-operative) cognitive function and resting-state electroencephalography could be used to identify patients at risk for POD. Pre-operative resting-state EEGs and the Montreal Cognitive Assessment (MoCA) were collected from 85 patients (age = 73 ± 6.4 years) undergoing elective surgery, 12 of whom subsequently developed POD. The model with the highest f1-score for predicting delirium, a linear-discriminant analysis (LDA) model incorporating MoCA scores and occipital alpha-band EEG features, was subsequently validated in an independent, prospective cohort of 51 older adults (age ≥ 60) undergoing elective surgery, 6 of whom developed POD. The LDA-based model, with a total of 7 features, was able to predict POD with area under the receiver operating characteristic curve, specificity and accuracy all >90%, and sensitivity > 80%, in the validation cohort. Notably, models incorporating both resting-state EEG and MoCA scores outperformed those including either EEG or MoCA alone. While requiring prospective validation in larger cohorts, these results suggest that prediction of POD with high accuracy may be feasible in clinical settings using simple and widely available clinical tools.

Background: Increasing healthcare costs require evidence-based resource use allocation for which assessing costs rigorously and comparably is crucial. Harmonized cross-country costing methods for evaluating interventions from a societal perspective are lacking. This study presents the development process and content of the service costing templates developed as part of the European project PECUNIA., Methods: The six developmental steps towards technological readiness of the templates included (1) a common conceptual costing framework and review of methodological costing issues, (2) harmonization strategy formulation, (3) proof-of-concept with expert feedback, (4) piloting, (5) validation, and (6) demonstration in six European countries., Results: The PECUNIA Reference Unit Cost (RUC) Templates for service costing are three new self-completion tools to be used with secondary or primary data for top-down micro-costing or top-down gross-costing approaches. Complementary data collection and unit cost aggregation/weighting templates are available. The applications leading to the final versions including (4) piloting through calculation of 15-unit costs, (5) validation within a Health Technology Assessment framework, and (6) RUC calculations mostly based on secondary data demonstrated the templates' general feasibility, with feedback for improved usability incorporated and a supplementary user guide developed., Conclusion: The validated PECUNIA RUC Templates for multi-sectoral and multi-country service costing allow for harmonized RUC development while incorporating flexibility and transparency in the choice of costing approaches, data sources and magnitude of remaining heterogeneity. The templates are expected to significantly improve the quality, comparability and availability of unit costs for economic evaluations, and promote the transferability of service cost information across Europe., (© 2024. The Author(s).)

Introduction: Long-term outcome in patients with prolonged weaning is known to be impaired, particularly against the background of their weaning status; however, data on their health-related quality of life (HRQL) are sparse., Methods: HRQL was measured in patients with prolonged weaning using the Severe Respiratory Insufficiency Questionnaire (SRI)., Results: Overall, 39 out of 83 patients with prolonged weaning filled in the SRI questionnaire. The median interval between discharge from hospital and HRQL assessment was 3.5 years (IQR 2.4-4.5 years). In the total group, the median SRI summary score was 56.4 (IQR 38.8-73.5). Patients with unsuccessful weaning and subsequent invasive home mechanical ventilation (N=15) had worse HRQL as estimated from the SRI summary score when compared to those with successful weaning both without (n=13) and with subsequent long-term non-invasive ventilation (NIV) (n=11); Kruskal-Wallis-Test: H (2, n=39) = 7,875446; P=0.0195. Statistically significant differences indicating worse HRQL in patients with invasive home mechanical ventilation were particularly evident in the following SRI subscales: Social relationships (P=0.0325), Anxiety (P=0.0096), and Psychological well-being (P=0.0079)., Conclusions: HRQL is substantially impaired in patients with unsuccessful prolonged weaning and subsequent invasive home mechanical ventilation compared to those with successful prolonged weaning. Further studies incorporating higher case numbers are needed to assess other conditions potentially affecting HRQL in patients with prolonged weaning., Competing Interests: Melanie Berger: kein Interessenkonflikt. Bernd Schönhofer: Honorarvorträge/Schulungstätigkeiten: Fisher & Pykel; Mandatsträger DGP. Andrea Paul: kein Interessenkonflikt. Stefan Suchi: kein Interessenkonflikt. Sarah Bettina Stanzel: Forschungsgelder: Löwenstein Medical; Forschungsvorhaben: Gemeinsamer Bundesausschuss. Wolfram Windisch: Honorarvorträge/Schulungstätigen: Löwenstein Medical; GCE Great Britain, Forschungsgelder: Löwenstein Medical; Forschungsvorhaben: GBA-Innovationsfond; Mandatsträger DGP. Maximilian Zimmermann: Honorarvorträge/Schulungstätigkeiten: Löwenstein Medical; Forschungsgelder: Löwenstein Medical., (Thieme. All rights reserved.)

The aim of this study was to investigate acute wound healing with dynamic optical coherence tomography (D-OCT). From 22 patients with 23 split skin graft donor sites, vessels at four wound edges, the wound bed, and adjacent and unaffected skin of the contralateral leg were measured by D-OCT at six time points from surgery to 4 weeks of healing. Changes in vessel orientation, density, diameter, morphology and pattern in horizontal, vertical and 3D images were analysed for wound healing and re-epithelialization. At 300 μm depth, there were significant differences of blobs and serpiginous vessels between normal and wounded skin. The wound had significantly more vertically oriented vessels, a higher degree of branching, vessel density and diameter compared with healthy skin. 3D images showed increased angiogenesis from healthy skin towards the wound centre, significantly higher vessel density at the wound than at normal skin and the highest at the interface. During wound healing blobs, coils and serpiginous vessels occurred significantly more frequently in lesional than healthy skin. Vessel density was greatest at the beginning, decreased and then increased by 4 weeks post-surgery. D-OCT helps to evaluate acute wound healing by visualizing and quantifying blood vessel growth in addition to re-epithelialization., (© 2024 The Author(s). International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

In rhinitis and asthma, several mHealth apps have been developed but only a few have been validated. However, these apps have a high potential for improving person-centred care (PCC), especially in allergen immunotherapy (AIT). They can provide support in AIT initiation by selecting the appropriate patient and allergen shared decision-making. They can also help in (i) the evaluation of (early) efficacy, (ii) early and late stopping rules and (iii) the evaluation of (carried-over) efficacy after cessation of the treatment course. Future perspectives have been formulated in the first report of a joint task force (TF)-Allergic Rhinitis and Its Impact on Asthma (ARIA) and the European Academy of Allergy and Clinical Immunology (EAACI)-on digital biomarkers. The TF on AIT now aims to (i) outline the potential of the clinical applications of mHealth solutions, (ii) express their current limitations, (iii) make proposals regarding further developments for both clinical practice and scientific purpose and (iv) suggest which of the tools might best comply with the purpose of digitally-enabled PCC in AIT., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Sleep disturbances are well-known symptoms of major depressive disorder (MDD). However, the prospective risk of MDD in the presence of sleep disturbances in a general population-based cohort is not well known. This study investigated associations between both polysomnography (PSG)-based or subjective sleep features and incident MDD. Participants representative of the general population who had never had MDD completed sleep questionnaires (n = 2000) and/or underwent PSG (n = 717). Over 8 years' follow-up, participants completed psychiatric interviews enabling the diagnosis of MDD. Survival Cox models were used to analyze associations between sleep features and MDD incidence. A higher Epworth Sleepiness Scale and presence of insomnia symptoms were significantly associated with a higher incidence of MDD (hazard ratio [HR] [95 % confidence interval (CI)]: 1.062 [1.022-1.103], p = 0.002 and 1.437 [1.064-1.940], p = 0.018, respectively). Higher density of rapid eye movements in rapid eye movement (REM) sleep was associated with a higher incidence of MDD in men (HR 1.270 [95 % CI 1.064-1.516], p = 0.008). In women, higher delta power spectral density was associated with a lower MDD incidence (HR 0.674 [95 % CI 0.463-0.981], p = 0.039). This study confirmed the associations between subjective and objective sleep features and the incidence of MDD in a large community dwelling cohort., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: We investigated the biological function of the mould allergen Alt a 1 as a carrier of micronutrients, such as the vitamin A metabolite retinoic acid (RA) and the influence of RA binding on its allergenicity in vitro and in vivo., Methods: Alt a 1-RA complex formation was analyzed in silico and in vitro. PBMCs from Alternaria-allergic donors were stimulated with Alt a 1 complexed with RA (holo-Alt a 1) or empty apo-Alt a 1 and analyzed for cytokine production and CD marker expression. Serum IgE-binding and crosslinking assays to apo- and holo-protein were correlated to B-cell epitope analysis. Female BALB/c mice already sensitized to Alt a 1 were intranasally treated with apo-Alt a 1, holo-Alt a 1 or RA alone before measuring anaphylactic response, serum antibody levels, splenic cytokines and CD marker expression., Results: In silico docking calculations and in vitro assays showed that the extent of RA binding depended on the higher quaternary state of Alt a 1. Holo-Alt a 1 loaded with RA reduced IL-13 released from PBMCs and CD3+CD4+CRTh2 cells. Complexing Alt a 1 to RA masked its IgE B-cell epitopes and reduced its IgE-binding capacity. In a therapeutic mouse model of Alternaria allergy nasal application of holo-Alt a 1, but not of apo-Alt a 1, significantly impeded the anaphylactic response, impaired splenic antigen-presenting cells and induced IL-10 production., Conclusion: Holo-Alt a 1 binding to RA was able to alleviate Th2 immunity in vitro, modulate an ongoing Th2 response and prevent anaphylactic symptoms in vivo, presenting a novel option for improving allergen-specific immunotherapy in Alternaria allergy., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

"State of the Art" Learning Objectives: This manuscript serves to provide the reader with a general overview of the contemporary approaches to peripheral nerve reconstruction as the field has undergone considerable advancement over the last 3 decades. The learning objectives are as follows: To provide the reader with a brief history of peripheral nerve surgery and some of the landmark developments that allow for current peripheral nerve care practices.To outline the considerations and management options for the care of patients with brachial plexopathy, spinal cord injury, and lower extremity peripheral nerve injury.Highlight contemporary surgical techniques to address terminal neuroma and phantom limb pain.Review progressive and future procedures in peripheral nerve care, such as supercharge end-to-side nerve transfers.Discuss rehabilitation techniques for peripheral nerve care., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2022 The Author(s).)

Background: Conditional logistic regression trees have been proposed as a flexible alternative to the standard method of conditional logistic regression for the analysis of matched case-control studies. While they allow to avoid the strict assumption of linearity and automatically incorporate interactions, conditional logistic regression trees may suffer from a relatively high variability. Further machine learning methods for the analysis of matched case-control studies are missing because conventional machine learning methods cannot handle the matched structure of the data., Results: A random forest method for the analysis of matched case-control studies based on conditional logistic regression trees is proposed, which overcomes the issue of high variability. It provides an accurate estimation of exposure effects while being more flexible in the functional form of covariate effects. The efficacy of the method is illustrated in a simulation study and within an application to real-world data from a matched case-control study on the effect of regular participation in cervical cancer screening on the development of cervical cancer., Conclusions: The proposed random forest method is a promising add-on to the toolbox for the analysis of matched case-control studies and addresses the need for machine-learning methods in this field. It provides a more flexible approach compared to the standard method of conditional logistic regression, but also compared to conditional logistic regression trees. It allows for non-linearity and the automatic inclusion of interaction effects and is suitable both for exploratory and explanatory analyses., (© 2024. The Author(s).)

Purpose: Heart valve disease is commonly treated by minimally invasive procedures with guide wires and catheterization. The main purpose of this study is to find out whether an extension of the guide wire with a sensor can support the surgeon within the blood vessel to reduce X-ray necessity., Methods: A smart guide wire is developed by an extension with a flex-bending sensor to evaluate the sensor signal with and without "blood" flow at a constant compression force. Various surgically relevant investigations are performed. For assessment, the mean temporal average of the moving averaged filtered ADC signal and a subsequent FFT are carried out., Results: Results show that there is a smaller sensor signal when the applied force or bending at the sensor is higher. In all investigations, there was a different sensor signal. The flex-bending sensor can detect the effect of pulsatile flow. The smallest temporal averaged signal difference between reference and clamp in the front wire's tip is 1.09%. For example, the mean temporal average of the filtered ADC signal for different clinically relevant scenarios is between 2550 and 2900., Conclusions: The results show that the sensorized guide wire developed for catheterization can support aortic valve implementation. The sensor sensitivity is sufficient to detect even very small variations within the blood vessel and therefore is promising to support catheterization heart valve surgeries in future., (© 2024. CARS.)

Tuberculosis (TB) causes major public health problems worldwide. Fighting TB requires sustained efforts in health prevention, diagnosis and treatment. Previous literature has shown that conventional diagnostic methods like X-ray and sputum microscopy often miss early or extrapulmonary TB due to their limited sensitivity. Blood tests, while useful, lack the anatomical detail needed for precise localization of TB lesions. A possible step forward in the fight against TB could be the use of Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and Computed Tomography (CT). This meta-analysis discusses the current literature, including the methods, results and implications of using FDG-PET-CT in the early diagnosis of TB. Analysis of the studies showed that the sensitivity of FDG-PET-CT as a potential method for early detection of TB was 82.6%., (© 2024. The Author(s).)

Background: This study explores the potential role of Thioredoxin-interacting protein (TXNIP) silencing in endothelial colony-forming cells (ECFCs) within the scope of age-related comorbidities and impaired vascular repair. We aim to elucidate the effects of TXNIP silencing on vasculogenic properties, paracrine secretion, and neutrophil recruitment under conditions of metabolic stress., Methods: ECFCs, isolated from human blood cord, were transfected with TXNIP siRNA and exposed to a high glucose and β-hydroxybutyrate (BHB) medium to simulate metabolic stress. We evaluated the effects of TXNIP silencing on ECFCs' functional and secretory responses under these conditions. Assessments included analyses of gene and protein expression profiles, vasculogenic properties, cytokine secretion and neutrophil recruitment both in vitro and in vivo. The in vivo effects were examined using a murine model of hindlimb ischemia to observe the physiological relevance of TXNIP modulation under metabolic disorders., Results: TXNIP silencing did not mitigate the adverse effects on cell recruitment, vasculogenic properties, or senescence induced by metabolic stress in ECFCs. However, it significantly reduced IL-8 secretion and consequent neutrophil recruitment under these conditions. In a mouse model of hindlimb ischemia, endothelial deletion of TXNIP reduced MIP-2 secretion and prevented increased neutrophil recruitment induced by age-related comorbidities., Conclusions: Our findings suggest that targeting TXNIP in ECFCs may alleviate ischemic complications exacerbated by metabolic stress, offering potential clinical benefits for patients suffering from age-related comorbidities., (© 2024. The Author(s).)

Background: Many countries observed a sharp decline in the use of general practice services after the outbreak of the COVID-19 pandemic. However, research has not yet considered how changes in healthcare consumption varied among regions with the same restrictive measures but different COVID-19 prevalence., Aim: To investigate how the COVID-19 pandemic affected healthcare consumption in Dutch general practice during 2020 and 2021, among regions with known heterogeneity in COVID-19 prevalence, from a pre-pandemic baseline in 2019., Design & Setting: Population-based cohort study using electronic health records. The study was undertaken in Dutch general practices involved in regional research networks., Method: An interrupted time-series analysis of changes in healthcare consumption from before to during the pandemic was performed. Descriptive statistics were used on the number of potential COVID-19-related contacts, reason for contact, and type of contact., Results: The study covered 3 595 802 contacts (425 639 patients), 3 506 637 contacts (433 340 patients), and 4 105 413 contacts (434 872 patients) in 2019, 2020, and 2021, respectively. Time-series analysis revealed a significant decrease in healthcare consumption after the outbreak of the pandemic. Despite interregional heterogeneity in COVID-19 prevalence, healthcare consumption decreased comparably over time in the three regions, before rebounding to a level significantly higher than baseline in 2021. Physical consultations transitioned to phone or digital over time., Conclusion: Healthcare consumption decreased irrespective of the regional prevalence of COVID-19 from the start of the pandemic, with the Delta variant triggering a further decrease. Overall, changes in care consumption appeared to reflect contextual factors and societal restrictions rather than infection rates., (Copyright © 2024, The Authors.)

Macular Telangiectasia Type 2 (MacTel) is a chronic, progressive disease of the central retina characterized by vascular and neurodegenerative changes. As there is currently no treatment for non-neovascular MacTel, there is a dearth for biomarkers identifying eyes with an increased risk for disease progression for patient counseling and clinical trial recruitment. Eyes were classified to be stable or progressive, defined by the fundus photography-based grading system by Gass and Blodi. First, structural differences between these two groups were assessed, employing optical coherence tomography (OCT) and OCT-angiography. Univariate regression analyses revealed evidence towards a lower superficial retinal layer (SRL) vessel density (VD), skeleton density (SD) and deep retinal layer (DRL) SD in progressing compared to stable eyes (p = 0.05, p = 0.05, p = 0.07). Second, a multivariable predictive model was employed to examine the predictive value of structural and functional parameters for disease progression. Baseline best corrected visual acuity (BCVA) and SRL SD are prognostic for disease progression (p < 0.001, p = 0.05). The presence of ellipsoid zone (EZ) loss is prognostic for future central retinal thickness (p < 0.01). We propose SRL SD, BCVA, and EZ loss as prognostic biomarkers and as possible outcome measures in future interventional studies in MacTel., (© 2024. The Author(s).)

Comprehensive molecular profiling by next generation sequencing (NGS) has revolutionized tumor classification and biomarker evaluation. However, routine implementation is challenged by the scant nature of diagnostic material obtained through minimally invasive procedures. Here, we describe our long-term experience in profiling cytology samples with an in-depth assessment of the performance, quality metrics, biomarker identification capabilities, and potential pitfalls. We highlight the impact of several optimization strategies to maximize performance with 4,871 prospectively sequenced clinical cytology samples tested by MSK-IMPACT ™ . Special emphasis is given to the use of residual supernatant cell free DNA (ScfDNA) as a valuable source of tumor DNA. Overall, cytology samples were similar in performance to surgical samples in identifying clinically relevant genomic alterations, achieving success rates up to 93% with full optimization. While cell block (CB) samples had excellent performance overall, low-level cross-contamination was identified in a small proportion of cases (4.7%), a common pitfall intrinsic to the processing of paraffin blocks, suggesting that more stringent precautions and processing modifications should be considered in quality control initiatives. By contrast ScfDNA samples had negligible contamination. Finally, ScfDNA testing exclusively used as a rescue strategy delivered successful results in 71% of cases where tumor tissue from CB was depleted.

Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8 + T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8 + T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy., (© 2024. The Author(s).)

A strict correlation among proximal tubule epithelial cell dysfunction, proteinuria, and modulation of the Renin-Angiotensin System and Kalikrein-Kinin System are crucial factors in the pathogenesis of Acute Kidney Injury (AKI). In this study, we investigated the potential protective effect of preconditioning by moderate-intensity aerobic exercise on gentamicin-induced AKI. Male Wistar rats were submitted to a moderate-intensity treadmill exercise protocol for 8 weeks, and then injected with 80 mg/kg/day s.c. gentamicin for 5 consecutive days. Four groups were generated: 1) NT+SAL (control); 2) NT+AKI (non-trained with AKI); 3) T+SAL (trained); and 4) T+AKI (trained with AKI). The NT+AKI group presented: 1) impairment in glomerular function parameters; 2) increased fractional excretion of Na  +  , K  +  , and water; 4) proteinuria and increased urinary γ-glutamyl transferase activity (a marker of tubular injury) accompanied by acute tubular necrosis; 5) an increased renal angiotensin-converting enzyme and bradykinin B1 receptor mRNA expression. Interestingly, the preconditioning by moderate-intensity aerobic exercise attenuated all alterations observed in gentamicin-induced AKI (T+AKI group). Taken together, our results show that the preconditioning by moderate-intensity aerobic exercise ameliorates the development of gentamicin-induced AKI. Our findings help to expand the current knowledge regarding the effect of physical exercise on kidneys during physiological and pathological conditions., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

In geminiviruses belonging to the genus Begomovirus, coat protein (CP) expression depends on viral AL2 protein, which derepresses and activates the CP promoter through sequence elements that lie within the viral intergenic region (IR). However, AL2 does not exhibit sequence-specific DNA binding activity but is instead directed to responsive promoters through interactions with host factors, most likely transcriptional activators and/or repressors. In this study, we describe a repressive plant-specific transcription factor, Arabidopsis thaliana TCP24 (AtTCP24), that interacts with AL2 and recognizes a class II TCP binding site in the CP promoter (GTGGTCCC). This motif corresponds to the previously identified conserved late element (CLE). We also report that histone 3 lysine 27 trimethylation (H3K27me3), an epigenetic mark associated with facultative repression, is enriched over the viral IR. H3K27me3 is deposited by Polycomb Repressive Complex 2 (PRC2), a critical regulator of gene expression and development in plants and animals. Remarkably, mutation of the TCP24 binding site (the CLE) in tomato golden mosaic virus (TGMV) and cabbage leaf curl virus (CaLCuV) CP promoters greatly diminishes H3K27me3 levels on viral chromatin and causes a dramatic delay and attenuation of disease symptoms in infected Arabidopsis and Nicotiana benthamiana plants. Symptom remission is accompanied by decreased viral DNA levels in systemically infected tissue. Nevertheless, in transient replication assays CLE mutation delays but does not limit the accumulation of viral double-stranded DNA, although single-stranded DNA and CP mRNA levels are decreased. These findings suggest that TCP24 binding to the CLE leads to CP promoter repression and H3K27me3 deposition, while TCP24-AL2 interaction may recruit AL2 to derepress and activate the promoter. Thus, a repressive host transcription factor may be repurposed to target a viral factor essential for promoter activity. The presence of the CLE in many begomoviruses suggests a common scheme for late promoter regulation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: The increased availability of myositis autoantibodies represents new possibilities and challenges in clinical practice (Lundberg IE, Tjärnlund A, Bottai M, Werth VP, Pilkington C, de Visser M, et al. 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis. 2017;76:1955-64. https://doi.org/10.1136/annrheumdis-2017-211468 .). The aim of this study was to perform a retrospective data analysis of patient cases with positive myositis autoantibodies to analyse their significance in routine rheumatology practice., Methods: A monocentric analysis of all the orders used to determine myositis autoantibodies from July 2019 to May 2022 in the Department of Rheumatology, Krankenhaus Porz am Rhein, Cologne, Germany, was carried out., Results: In the defined time interval, a total of 71,597 laboratory values for the antibodies mentioned above were obtained. A total of 238 different positive autoantibodies ​​were detected in 209 patients. Idiopathic inflammatory myopathy was diagnosed in 37 patients (18%), and inflammatory rheumatic diseases other than idiopathic inflammatory myopathy were diagnosed in 90 patients (43%). No inflammatory rheumatic disease was diagnosed in 82 patients (39%). General clusters of clinical manifestations were observed., Conclusions: In our cohort, we were able to show that a relevant proportion of patients with positive myositis antibodies did not have idiopathic inflammatory myopathies or inflammatory rheumatic diseases. This finding indicates the importance of myositis autoantibodies in this group of patients. However, further studies on the course of symptoms and examination results in patients without inflammatory rheumatic diseases and with positive myositis antibodies are necessary., (© 2024. The Author(s).)

Purpose: Shared decision-making (SDM) is a method for a patient and physician to cooperatively consider a diagnostic or therapeutic option, ultimately empowering the patient to make an informed decision. Atrial fibrillation (AF) ablation is a procedure that would benefit from SDM given the risk of serious adverse events, the high rate of arrhythmia recurrence, and alternative treatment options. Implementing a patient decision aid (PDA) may help facilitate AF ablation SDM by succinctly conveying important information to patients., Methods: Patients scheduled for initial AF catheter ablation were randomized to a virtual SDM visit utilizing a PDA, which covered procedural risks and benefits, or a virtual control visit with a tool outlining periprocedural processes. Preoperatively, patients completed a questionnaire assessing procedural risk and benefit knowledge, as well as perceived involvement with the decision-making process. Unpaired t-tests were used to compare groups., Results: The SDM group scored significantly better overall on knowledge-based questions compared to the control group (69% correct [n=34] vs 53% [n=32]; P=0.00013). In particular, the SDM group was significantly more likely to answer questions correctly about stroke risk (P=0.01), anticoagulation (P=0.01), and potential need for additional procedures (P=0.03 and P=0.03). Perceived involvement in the decision-making process was overall not improved with PDA use (4.7 vs 4.6 out of 5; P=0.72)., Conclusions: The addition of a PDA for AF ablation significantly improved procedural knowledge but did not impact patients' perceived involvement in the decision-making process compared to traditional preprocedural discussion alone., Competing Interests: Conflicts of Interest: None., (© 2024 Advocate Aurora Health, Inc.)

Aims: Inflammation accompanies heart failure (HF) and elevated levels of inflammatory biomarkers are linked to new onset of HF. However, whether the prognostic relevance of inflammatory biomarkers is different in HF with reduced (HFrEF) and preserved ejection fraction (HFpEF) is unclear. The aim of the current study is to explore the role of inflammation on the mortality risk in patients with HF., Methods: We analysed interleukin-6 and hsCRP levels by ELISA and immunonephelometry, respectively, in HFpEF and HFrEF patients referred for coronary angiography and assessed the prognostic value in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study., Results: HF was present in 1086 patients (N = 506 HFpEF; N = 580 HFrEF; mean age 65 ± 10 years; 28% female). Increasing IL-6 levels were significantly associated with increased CV mortality in HFpEF [1.5 (95% CI: 1.1-2.2), P = 0.018] but not HFrEF [HR 1.3 (95% CI: 1.0-1.7), P = 0.06] patients. High-sensitive CRP followed a similar pattern but failed to reach statistical significance after full-adjustment (HFpEF: HR 1.4 95%C I: 1.0-2.0; P = 0.065; HFrEF HR: 1.0 95% CI: 0.7-1.3; P = 0.800). Interaction analysis in patients stratified by IL-6 and N terminal pro brain natriuretic peptide (NT-proBNP) above and below the median revealed a stepwise increase in CV-mortality in HFpEF (P = 0.036) but not HFrEF patients (P = 0.220). To investigate the relationship between IL-6 and NT-proBNP, we assessed the genetic IL6-Receptor variant p.Asp358Ala (rs2228145) which is linked to impaired IL-6 receptor signalling. Homozygous carriers with HFpEF but not HFrEF exhibited significantly lower NT-pro-BNP levels compared with wildtype carriers (HFpEF 779 pg/mL ± 787 vs. 1180 pg/ mL ± 1532; P = 0.008; HFrEF 2289 pg/ mL ± 3439 vs. 2326 pg/ mL ± 3386; P = 0.94), raising the hypothesis that IL-6 signalling may play a pathophysiological role in HFpEF., Conclusions: These data suggest a predictive value of elevated IL-6 for CV-mortality in HFpEF but not in HFrEF patients., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Although asexuality became a growing research subject over the last decade, data on the mental health of individuals identifying as asexual is still rare. The key objective of the present study was to examine depressive symptoms among individuals identifying as asexual. Data of LGBTQIA+ (Lesbian, Gay, Bi-sexual, Trans*, Queer, Inter*, Asexual and/or + indicating others within the community) and cisgender heterosexual individuals was collected through an online survey during the COVID-19 lockdowns in Germany. The survey included questions about sexual and gender identity, depressive symptoms, and asexual identity. An analysis of N = 6601 participants was conducted. A total of n = 445 individuals identified as asexual. Regression results indicated identifying as asexual being significantly associated with higher depressive symptoms. Results suggest that individuals identifying as asexual represent a vulnerable group within the group of sexual minorities, one that fundamentally requires special psychosocial support, especially in times of pandemics., (© 2024. The Author(s).)

Tuberculosis remains a significant global health challenge. Tuberculosis affects millions of individuals worldwide. Early detection of tuberculosis plays a relevant role in the management of treatment of tuberculosis. This systematic review will analyze the findings of several published studies on the topic of the early detection of tuberculosis. This systematic review highlights their methodologies and limitations as well as their contributions to our understanding of this pressing issue. Early detection of tuberculosis can be achieved through tuberculosis screening for contacts. Comprehensive health education for household contacts can be used as early detection. The in-house deep learning models can be used in the X-ray used for automatic detection of tuberculosis. Interferon gamma release assay, routine passive and active case detection, portable X-ray and nucleic acid amplification testing, and highly sensitive enzyme-linked immunosorbent assay tests play critical roles in improving tuberculosis detection., (© 2024. The Author(s).)

Capsules are long-chain carbohydrate polymers that envelop the surfaces of many bacteria, protecting them from host immune responses. Capsule biosynthesis enzymes are potential drug targets and valuable biotechnological tools for generating vaccine antigens. Despite their importance, it remains unknown how structurally variable capsule polymers of Gram-negative pathogens are linked to the conserved glycolipid anchoring these virulence factors to the bacterial membrane. Using Actinobacillus pleuropneumoniae as an example, we demonstrate that CpsA and CpsC generate a poly(glycerol-3-phosphate) linker to connect the glycolipid with capsules containing poly(galactosylglycerol-phosphate) backbones. We reconstruct the entire capsule biosynthesis pathway in A. pleuropneumoniae serotypes 3 and 7, solve the X-ray crystal structure of the capsule polymerase CpsD, identify its tetratricopeptide repeat domain as essential for elongating poly(glycerol-3-phosphate) and show that CpsA and CpsC stimulate CpsD to produce longer polymers. We identify the CpsA and CpsC product as a wall teichoic acid homolog, demonstrating similarity between the biosynthesis of Gram-positive wall teichoic acid and Gram-negative capsules., (© 2024. The Author(s).)

Background: Diagnostic testing is prevalent among children with persistent non-specific symptoms (PNS), and both undertesting and overtesting have negative consequences for child and society. Research in adults with PNS has shown that general practitioners (GPs) use diagnostic testing for reasons other than diagnosis, but comparable research has not been conducted in children. Understanding GPs' perspectives of testing decisions in children could provide insights into mechanisms of undertesting and overtesting., Aim: To investigate GPs' perspectives of conducting or refraining from diagnostic testing in children with PNS, and differences with motives in adults., Design and Setting: Qualitative study using semi-structured interviews with Dutch GPs., Method: We purposively sampled GPs until data saturation. Reasons for conducting or refraining from diagnostic tests were explored using two real-life cases from daily practice. Online video interviews were transcribed verbatim. Data were collected and analyzed concurrently by thematic content analysis., Findings: Twelve GPs participated. Their decision-making involved a complex trade-off among four themes: medical (e.g., alarm symptoms), psychosocial (e.g., doctor-patient relationship), consultation management (e.g., 'quick fix'), and efficient resource utilization (e.g., sustainability). Compared to adults, GPs were more hesitant to conduct diagnostic testing in children due to their higher vulnerability to fearing invasive procedures, lower probability of organic disease, and reduced autonomy., Conclusion: As in adults, GPs' decisions to conduct diagnostic tests in children were motivated by reasons beyond diagnostic uncertainty. Educational programs, interventions, and guidelines that aim to change the testing behaviors of GPs in children with PNS should target these reasons as well., (Copyright © 2024, The Authors.)

The pivotal role of human endometrial stromal cells (hESCs) in the development of endometriosis lies in their ability to adopt a pro-invasive and proinflammatory profile upon migration to areas outside the uterus. However, the molecular mechanisms involved in these events remain unclear. In this study, we investigated how angiotensin II (Ang II) affects the plasminogen-plasmin system in hESCs, and the mechanisms underlying cell proliferation, migration, matrix degradation, and inflammation. Precursors, receptors, and peptidases involved in angiotensin metabolism increased significantly in Ang II-treated hESCs. The expression and activity of tissue (tPA)- and urokinase (uPA)- type plasminogen activators and the receptor for uPA (uPAR) were induced in the presence of Ang II. The up-regulation of tPA-uPA/uPAR pathway significantly contributes to heightened plasmin production both on the surface of hESCs and in their conditioned media. As a result, the plasmin generation induced by Ang II enhances the degradation of fibrin and matrix proteins, while also boosting hESC viability, proliferation, and migration through the up-regulation of growth factor expression. Notably, Ang II-induced hESC migration was dependent on the generation of active plasmin on cell surface. Ang II regulates oxidative and inflammatory signalling in hESCs primarily via NADPH oxidase and through the up-regulation of proinflammatory cytokines and adhesion molecules. Interestingly, Ang II receptor (AT1R) blockage, decreased plasmin generation, tPA-uPA/uPAR expression and hESC migration. Our results suggest that Ang II/AT1R axis regulates hESC proliferation and migration through tPA-uPA/uPAR pathway activation and plasmin generation. We propose the Ang II/AT1R axis as a potential target for endometriosis treatment., 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 Elsevier Inc. All rights reserved.)

Background: Most patients after transcatheter aortic valve replacement (TAVR) are admitted directly to the cardiac intensive care unit (CICU) despite low complication rates. Reducing unnecessary CICU hospitalization reduces healthcare costs. This study aimed to compare the outcomes between patients admitted directly to the cardiology department (CD) and those admitted to CICU based on prespecified protocols., Methods: Historical cohort study of all patients who underwent TAVR and were admitted directly to the CD according to a prespecified protocol (uncomplicated procedure, hemodynamically stable, without new conduction abnormalities) in 2017-2018, and the same number of patients meeting the same criteria who were admitted to the CICU in 2015-2016 before direct CD admission was initiated. Pacemaker implantation during the procedure was not considered a new conduction abnormality. In-hospital outcomes and 30-day post-discharge outcomes were compared., Results: Overall, 260 patients (130 CICU + 130 CD) were included in the study. There was no in-hospital mortality in either group, and the post-procedure length of stay was shorter for patients admitted to CD (median and IQR: 2, 2-4 vs. 4, 3-5 days, p <0.001). There was no significant difference in 30-day emergency department visits between groups (CICU:13.9% vs. CD:16.2%, p = 0.602), rehospitalization rate (9.3%) was the same in both groups, and one patient from the CICU group died. Similar results were observed in multivariable analysis and after matching., Conclusion: Direct admission to the CD after TAVR, according to the proposed criteria, may be considered as a safe and less expensive alternative for stable patients after an uncomplicated TAVR procedure., Competing Interests: Conflict of interests Nothing to disclose., (Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

In the rapidly evolving digital radiology landscape, a surge in solutions has emerged including more than 500 artificial intelligence applications that have received 510 k clearance by the FDA. Moreover, there is an extensive number of non-regulated applications, specifically designed to enhance workflow efficiency within radiology departments. These efficiency applications offer tremendous opportunities to resolve operational pain points and improve efficiency for radiology practices worldwide. However, selecting the most effective workflow efficiency applications presents a major challenge due to the multitude of available solutions and unclear evaluation criteria. In this article, we share our perspective on how to structure the broad field of workflow efficiency applications and how to objectively assess individual solutions. Along the different stages of the radiology workflow, we highlight 31 key operational pain points that radiology practices face and match them with features of workflow efficiency apps aiming to address them. A framework to guide practices in assessing and curating workflow efficiency applications is introduced, addressing key dimensions, including a solution's pain point coverage, efficiency claim strength, evidence and credibility, ease of integration, and usability. We apply this framework in a large-scale analysis of workflow efficiency applications in the market, differentiating comprehensive workflow efficiency ecosystems seeking to address a multitude of pain points through a unified solution from workflow efficiency niche apps following a targeted approach to address individual pain points. Furthermore, we propose an approach to quantify the financial benefits generated by different types of applications that can be leveraged for return-on-investment calculations., (© 2024. The Author(s).)

Background: Unhealthy eating habits are costly and can lead to serious diseases such as obesity. Nutrition apps offer a promising approach to improving dietary behavior. Gamification elements (GEs) can motivate users to continue using nutrition apps by making them more enjoyable, which can lead to more positive behavioral changes regarding dietary choices. However, the effects of users' preferences and individual characteristics on gamified systems are not yet understood. Current calls for research suggest that personalized gamified systems might lead to user satisfaction, continuous app use, and-ultimately-long-term improvements in diet., Objective: The aim was to determine the most preferred GEs in nutrition apps and to define clusters of GEs preferences in terms of personality and socio-demographic characteristics., Methods: We surveyed 308 people to measure their preferences regarding GEs in nutrition apps and applied best-worst scaling to determine the most preferred GEs. Furthermore, we used cluster analysis to identify different user clusters and described them in terms of personality and socio-demographic characteristics., Results: We determine that GEs most favored are goals, progress bars, and coupons. We revealed three distinct user clusters in terms of personality and socio-demographic characteristics. Based on the individual factors of openness and self-perception, we find that significant differences exist between the preferences for leaderboards and coupons., Conclusion: We contribute by shedding light on differences and similarities in GE preferences relating to specific contexts and individual factors, revealing the potential for individualized nutrition apps. Our findings will benefit individuals, app designers, and public health institutions., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Purpose: The Treatment exit Options For non-infectious Uveitis (TOFU) registry documents disease courses for non-anterior non-infectious uveitis entities with and without treatment to generate more evidence for clinical management recommendations including treatment exit strategies. In this article, we present the participants' baseline characteristics after the first 3 years., Methods: TOFU is an observational, prospective registry and recruits patients ≥18 years of age with non-anterior non-infectious uveitis with or without a history of previous disease-modifying antirheumatic drugs (DMARDs) treatment. The data are collected in the electronic data capture software REDCap and include ophthalmological and general medical history as well as clinical findings., Results: Between 24.10.2019 and 27.12.2022, 628 patients were enrolled at 25 clinical sites in Germany and Austria. Patients with intermediate uveitis were most frequently included (n=252; 40.1%) followed by posterior uveitis (181; 28.8%), panuveitis (n=154; 24.5%) and retinal vasculitis (n=41, 6.5%). At baseline, 39.6% were treated with systemic corticosteroids, 22.3% with conventional synthetic (cs) DMARDs, 20.5% with biological (b) DMARDs and 3.6% with other systemic treatments. Average best corrected visual acuity (BCVA) was 0.69 decimal. Patients with panuveitis had the worst BCVA with 0.63 decimal. Overall, only 8 patients (1.3%) suffered from severe visual impairment., Conclusions: Less than half of participants required DMARD treatment at baseline, with csDMARDs used more frequently than bDMARDs. The presence of severe visual impairment was low, mostly affecting patients with panuveitis. These findings are in line with comparable monocentric cross-sectional studies of tertiary uveitis centres in Germany and will allow us to generate generalisable evidence in TOFU., Competing Interests: Competing interests: CH is a consultant for Alimera Sciences (Aldershot, Hampshire, UK) and received Honoria from AbbVie and Novartis. MWMW is a consultant for Heine Optotechnik GmbH and glaucare GmbH, has received honoraria from ASKIN & CO GmbH, Bayer AG, Berlin-Chemie AG, Heidelberg Engineering, Novartis Pharma GmbH, Pro Generika e.V., Eyepress Fachmedien GmbH, and Science Consulting in Diabetes GmbH, and research funding from CenterVue SpA, Carl Zeiss Meditec, and Novartis Pharma GmbH. RPF is a consultant for Alimera, Apellis, Biogen, Böhringer-Ingelheim, Bayer, Caterna, Novartis, ODOS, ProGenerika, Roche/Genentech, has received honoraria from Roche and research funding from Biogen. He is member of the advisory board of Stada Pharm, Roche and Opthea. CMED is a member of the advisory board of Alimera and he has received honoraria from AbbVie, Novartis, Santen and Thea. His institution received funding for clinical trials from Tarsier and Roche. UP received study support from Abbvie and honoraria from Abbvie, Alimera and Novartis. None of the following authors have any proprietary interests or conflicts of interest related to this submission: DJF, JD, TH, MB, MS, HR, KTB and TKL., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Blood clot formation, a crucial process in hemostasis and thrombosis, has garnered substantial attention for its implications in various medical conditions. Microscopic examination of blood clots provides vital insights into their composition and structure, aiding in the understanding of clot pathophysiology and the development of targeted therapeutic strategies. This study explores the use of topological data analysis (TDA) to assess plasma clot characteristics microscopically, focusing on the identification of the elements components, holes and Wasserstein distances. This approach should enable researchers to objectively classify fibrin networks based on their topologic architecture. We tested this mathematical characterization approach on plasma clots formed in static conditions from porcine and human citrated plasma samples, where the effect of dilution and direct thrombin inhibition was explored. Confocal microscopy images showing fluorescence labeled fibrin networks were analyzed. Both treatments resulted in visual differences in plasma clot architecture, which could be quantified using TDA. Significant differences between baseline and diluted samples, as well as blood anticoagulated with argatroban, were detected mathematically. Therefore, TDA could be indicative of clots with compromised stability, providing a valuable tool for thrombosis risk assessment. In conclusion, microscopic examination of plasma clots, coupled with Topological Data Analysis, offers a promising avenue for comprehensive characterization of clot microstructure. This method could contribute to a deeper understanding of clot pathophysiology and thereby refine our ability to assess clot characteristics., (© 2024. The Author(s).)

A Gram-negative, aerobic, pink-pigmented, and bacteriochlorophyll a -containing bacterial strain, designated B14 T , was isolated from the macroalga Fucus spiralis sampled from the southern North Sea, Germany. Based on 16S rRNA gene sequences, species of the genera Roseobacter and Sulfitobacter were most closely related to strain B14 T with sequence identities ranging from 98.15 % ( Roseobacter denitrificans Och 114 T ) to 99.11 % ( Roseobacter litoralis Och 149 T ), whereas Sulfitobacter mediterraneus CH-B427 T exhibited 98.52 % sequence identity. Digital DNA-DNA hybridization and average nucleotide identity values between the genome of the novel strain and that of closely related Roseobacter and Sulfitobacter type strains were <20 % and <77 %, respectively. The novel strain contained ubiquinone-10 as the only respiratory quinone and C 18 : 1  ω7 c , C 16 : 0 , C 18 : 0 , C 12 : 1  ω7 c , C 18 : 2  ω7,13 c , and C 10 : 0 3-OH as the major cellular fatty acids. The predominant polar lipids of strain B14 T were phosphatidylcholine, phosphatidylethanolamine, and phosphatidylglycerol. The genome of strain B14 T comprises a chromosome with a size of 4.5 Mbp, one chromid, and four plasmids. The genome contains the complete gene cluster for aerobic anoxygenic photosynthesis required for a photoheterotrophic lifestyle. The results of this study indicate that strain B14 T (=DSM 116946 T =LMG 33352 T ) represents a novel species of the genus Roseobacter for which the name Roseobacter fucihabitans sp. nov. is proposed.

Purpose: Patients with metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC) are effectively treated with entrectinib, a multikinase inhibitor. Whether serial targeted gene panel sequencing of cell-free DNA (cfDNA) can identify response and progression along with mechanisms of acquired resistance to entrectinib is underexplored., Methods: In patients with ROS1 fusion-positive NSCLC, coclinical trial plasma samples were collected before treatment, after two cycles, and after progression on entrectinib (global phase II clinical trial, ClinicalTrials.gov identifier: NCT02568267). Samples underwent cfDNA analysis using MSK-ACCESS. Variant allele frequencies of detectable alterations were correlated with objective response per RECIST v1.1 criteria., Results: Twelve patients were included, with best response as partial response (n = 9, 75%), stable disease (n = 2, 17%), and progressive disease (PD; n = 1, 8%). A ROS1 fusion was variably detected in cfDNA; however, patients without a ROS1 fusion in cfDNA had no other somatic alterations detected, indicative of possible low cfDNA shedding. Clearance of the enrolling ROS1 fusion or concurrent non- ROS1 alterations ( TP53 , CDH1 , NF1 , or ARID1A mutations) was observed in response to entrectinib therapy. Radiologic PD was accompanied by redemonstration of a ROS1 fusion or non- ROS1 alterations. On-target resistance was rare; only one patient acquired ROS1 G2032R at the time of progression. Several patients acquired new off-target likely oncogenic alterations, including a truncating alteration in NF1 ., Conclusion: Serial cfDNA monitoring may complement radiographic assessments as determinants of response and resistance to entrectinib in ROS1 fusion-positive lung cancers in addition to detecting putative resistance mechanisms on progression.

Purpose: Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised hosts. Early monotherapy with direct-acting antivirals or monoclonal antibodies, as recommended by the international guidelines, does not prevent this with certainty. Dual therapies may therefore have a synergistic effect., Methods: This retrospective, multicentre study compared treatment strategies for corona virus disease-19 (COVID-19) with combinations of nirmatrelvir/ritonavir, remdesivir, molnupiravir, and/ or mABs during the Omicron surge. Co-primary endpoints were prolonged viral shedding (≥ 10 6 copies/ml at day 21 after treatment initiation) and days with SARS-CoV-2 viral load ≥ 10 6 copies/ml. Therapeutic strategies and risk groups were compared using odds ratios and Fisher's tests or Kaplan-Meier analysis and long-rank tests. Multivariable regression analysis was performed., Results: 144 patients were included with a median duration of SARS-CoV-2 viral load ≥ 10 6 copies/ml of 8.0 days (IQR 6.0-15.3). Underlying haematological malignancies (HM) (p = 0.03) and treatment initiation later than five days after diagnosis (p < 0.01) were significantly associated with longer viral shedding. Prolonged viral shedding was observed in 14.6% (n = 21/144), particularly in patients with underlying HM (OR 3.5; 95% CI 1.2-9.9; p = 0.02). Clinical courses of COVID-19 were mild to moderate with only few adverse effects potentially related to combination treatment., Conclusion: Early combination treatment of COVID-19 effectively prevented prolonged viral shedding in 85.6% of cases. Considering the rapid viral clearance rates and low toxicity, individualized dual therapy approaches may be beneficial in high-risk patients., (© 2023. The Author(s).)

Blood-feeding behavior has independently evolved in arthropods multiple times. Unlike hard ticks, soft ticks employ a rapid-feeding strategy for hematophagy, and there are comparatively limited studies on the transcriptomes of these organisms. This study investigates the soft tick Ornithodoros hermsi, conducting histopathological examinations at bitten skin sites and tick whole-body transcriptomic analyses across various developmental and feeding stages, including larvae, 1st-nymphal, and 2nd-nymphal stages. The results revealed the ability of O. hermsi to induce skin hemorrhage at the bite sites. Transcriptomic analyses identified three consistent transcriptional profiles: unfed, early-fed (6 h, 12 h, 24 h), and late-fed (5 days). The unfed profile exhibited high transcriptional activity across most of the functional classes annotated. In contrast, early-fed stages exhibited decreased expression of most functional classes, except for the unknown, which is highly expressed. Finally, transcriptional expression of most functional classes increased in the late-fed groups, resembling the baseline expression observed in the unfed groups. These findings highlight intense pre-feeding transcriptional activity in O. hermsi ticks, aligning with their rapid-feeding strategy. Moreover, besides shedding light on the temporal dynamics of key pathways during blood meal processing and tick development, this study contributes significantly to the transcriptome repertoire of a medically relevant soft tick species with relatively limited prior knowledge., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The world-wide prevalence of insomnia disorder reaches up to 10% of the adult population. Women are more often afflicted than men, and insomnia disorder is a risk factor for somatic and mental illness, especially depression and anxiety disorders. Persistent hyperarousals at the cognitive, emotional, cortical and/or physiological levels are central to most theories regarding the pathophysiology of insomnia. Of the defining features of insomnia disorder, the discrepancy between minor objective polysomnographic alterations of sleep continuity and substantive subjective impairment in insomnia disorder remains enigmatic. Microstructural alterations, especially in rapid eye movement sleep ("rapid eye movement sleep instability"), might explain this mismatch between subjective and objective findings. As rapid eye movement sleep represents the most highly aroused brain state during sleep, it might be particularly prone to fragmentation in individuals with persistent hyperarousal. In consequence, mentation during rapid eye movement sleep may be toned more as conscious-like wake experience, reflecting pre-sleep concerns. It is suggested that this instability of rapid eye movement sleep is involved in the mismatch between subjective and objective measures of sleep in insomnia disorder. Furthermore, as rapid eye movement sleep has been linked in previous works to emotional processing, rapid eye movement sleep instability could play a central role in the close association between insomnia and depressive and anxiety disorders., (© 2024 The Author(s). Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Background: Free open-access medical education (FOAM) is extremely popular among learners and educators despite lacking the traditional peer review process. Despite the potential for inaccurate, low-quality, or biased content, little has been published describing FOAM authors., Methods: We performed a cross-sectional analysis of 12 months of content from the top 25 blogs in the 2020 Social Media Index from August 2020-2021. We recorded the number of posts per site and descriptive characteristics of authors, including gender affiliation, conflicts of interest (COI) statements, and type of practice (academic, community, or hybrid)., Results: We identified 2141 posts by 1001 authors. More than half were produced by six websites: EM Docs (266), Life in the Fast Lane (232), EMCrit (188), ALiEM (185), Don't Forget the Bubbles (181), and Rebel EM (174). Most content (1680 posts, 78.5%) lacked a COI statement. Authors were mostly academic (89%), mostly held MD degrees (67.4%), and were mostly men (59.7%). Geographically, most FOAM authors reside in the United States (59.5%), Canada (22.42%), or the United Kingdom (9.4%)., Conclusions: Of all the posts in the top 25 sites in 2020, more than half came from six sites, and authors were largely North American men in academics with MD degrees. Learners, content creators, and educators should consider the ways in which a more diverse authorship pool might bring value to the FOAM educational experience., Competing Interests: The authors declare no conflicts of interest. All authors had full access to all the study data and had final responsibility for the decision to submit for publication., (© 2024 The Author(s). AEM Education and Training published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)