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Janosch A Priebe,1 Linda Kerkemeyer,2 Katharina K Haas,1 Katharina Achtert,2 Leida F Moreno Sanchez,1,3 Paul Stockert,1 Maximilian Spannagl,1 Julia Wendlinger,1 Reinhard Thoma,4 Siegfried Ulrich Jedamzik,3 Jan Reichmann,5 Sebastian Franke,6 Leonie Sundmacher,6 Volker E Amelung,2 Thomas R Toelle1 1Center of Interdisciplinary Pain Medicine, Department of Neurology, Klinikum Rechts der Isar, Technical University of Munich (TUM), Munich, Germany; 2Institute for Applied Health Services Research, Inav GmbH, Berlin, Germany; 3Bayerische TelemedAllianz, Ingolstadt, Baar-Ebenhausen, Germany; 4Pain Clinic, Algesiologikum Pain Center, Munich, Germany; 5StatConsult GmbH Magdeburg, Magdeburg, Germany; 6Department of Health Economics, Faculty of Sports and Health Sciences, Technical University of Munich (TUM), Munich, GermanyCorrespondence: Thomas R Toelle, Center of Interdisciplinary Pain Medicine, Department of Neurology, Klinikum rechts der Isar, Technical University of Munich (TUM), Ismaninger Str. 22, Munich, 81675, Germany, Tel +49-89-4140-4613, Email thomas.toelle@tum.dePurpose: Non-specific low back pain (NLBP) exerts a profound impact on global health and economics. In the era of Web 3.0, digital therapeutics offer the potential to improve NLBP management. The Rise-uP trial introduces a digitally anchored, general practitioner (GP)-focused back pain management approach with the Kaia back pain app as the key intervention. Here, we present the 12-months evaluation of the Rise-uP trial including clinical and economic outcomes, patient satisfaction and behavioral tracking analysis.Methods: The cluster-randomized controlled study (registration number: DRKS00015048) enrolled 1237 patients, with 930 receiving treatment according to the Rise-uP approach and 307 subjected to standard of care treatment. Assessments of pain, psychological state, functional capacity, and well-being (patient-reported outcome measures; PROMs) were collected at baseline, and at 3-, 6-, and 12-months follow-up intervals. Health insurance partners AOK, DAK, and BARMER provided individual healthcare cost data. An artificial intelligence (AI)-driven behavioral tracking analysis identified distinct app usage clusters that presented all with about the same clinical outcome. Patient satisfaction (patient-reported experience measures; PREMs) was captured at the end of the trial.Results: Intention-to-treat (ITT) analysis demonstrated that the Rise-uP group experienced significantly greater pain reduction at 12 months compared to the control group (IG: − 46% vs CG: − 24%; p < 0.001) with only the Rise-uP group achieving a pain reduction that was clinically meaningful. Improvements in all other PROMs were notably superior in patients of the Rise-uP group. The AI analysis of app usage discerned four usage clusters. Short- to long-term usage, all produced about the same level of pain reduction. Cost-effectiveness analysis indicated a substantial economic benefit for Rise-uP.Conclusion: The Rise-uP approach with a medical multimodal back pain app as the central element of digital treatment demonstrates both, clinical and economic superiority compared to standard of care in the management of NLBP.Keywords: digital medicine, medical apps, non-specific low back pain, multimodal pain therapy, healthcare costs, behavioral tracking analysis

The human placenta exhibits a complex three-dimensional (3D) structure with a interpenetrating vascular tree and large internal interfacial area. In a unique and yet insufficiently explored way, this parenchymal structure enables its multiple functions as a respiratory, renal, and gastrointestinal multiorgan. The histopathological states are highly correlated with complications and health issues of mother, and fetus or newborn. Macroscopic and microscopic examination has so far been challenging to reconcile on the entire organ. Here we show that anatomical and histological scales can be bridged with the advent of hierarchical phase-contrast tomography and highly brilliant synchrotron radiation. To this end, we are exploiting the new capabilities offered by the BM18 beamline at ESRF, Grenoble for whole organ as well as the coherence beamline P10 at DESY, Hamburg for high-resolution, creating unique multiscale datasets. We also show that within certain limits, translation to μ CT instrumentation for 3D placenta examination becomes possible based on advanced preparation and CT protocols, while segmentation of the datasets by machine learning now remains the biggest challenge., (© The Author(s) 2025. Published by Oxford University Press on behalf of National Academy of Sciences.)

X-ray Phase Contrast Tomography (XPCT) based on wavefield propagation has been established as a high resolution three-dimensional (3D) imaging modality, suitable to reconstruct the intricate structure of soft tissues, and the corresponding pathological alterations. However, for biomedical research, more is needed than 3D visualisation and rendering of the cytoarchitecture in a few selected cases. First, the throughput needs to be increased to cover a statistically relevant number of samples. Second, the cytoarchitecture has to be quantified in terms of morphometric parameters, independent of visual impression. Third, dimensionality reduction and classification are required for identification of effects and interpretation of results. To address these challenges, we here design and implement a novel integrated and high throughput XPCT imaging and analysis workflow for 3D histology, pathohistology and drug testing. Our approach uses semi-automated data acquisition, reconstruction and statistical quantification. We demonstrate its capability for the example of lung pathohistology in Covid-19. Using a small animal model, different Covid-19 drug candidates are administered after infection and tested in view of restoration of the physiological cytoarchitecture, specifically the alveolar morphology. To this end, we then use morphometric parameter determination followed by a dimensionality reduction and classification based on optimal transport. This approach allows efficient discrimination between physiological and pathological lung structure, thereby providing quantitative insights into the pathological progression and partial recovery due to drug treatment. Finally, we stress that the XPCT image chain implemented here only used synchrotron radiation for validation, while the data used for analysis was recorded with laboratory μ CT radiation, more easily accessible for pre-clinical research., (© 2024. The Author(s).)

A minimal diffusion barrier is key to the pulmonary gas exchange. In alveolar capillary dysplasia (ACD), a rare genetically driven disease of early infancy, this crucial fibrovascular interface is compromised while the underlying pathophysiology is insufficiently understood. Recent in-depth analyses of vascular alterations in adult lung disease encouraged researchers to extend these studies to ACD and compare the changes of the microvasculature. Lung tissue samples of children with ACD (n = 12), adults with non-specific interstitial pneumonia (n = 12), and controls (n = 20) were studied using transmission electron microscopy, single-gene sequencing, immunostaining, exome sequencing, and broad transcriptome profiling. In ACD, pulmonary capillary basement membranes were hypertrophied, thickened, and multilamellated. Transcriptome profiling revealed increased CDH5, COL4A1, COL15A1, PTK2B, and FN1 and decreased VIT expression, confirmed by immunohistochemistry. In contrast, non-specific interstitial pneumonia samples showed a regular basement membrane architecture with preserved VIT expression but also increased COL15A1 + vessels. This study provides insight into the ultrastructure and pathophysiology of ACD. The lack of normally developed lung capillaries appeared to cause a replacement by COL15A1 + vessels, a mechanism recently described in interstitial lung disease. The VIT loss and FN1 overexpression might contribute to the unique appearance of basement membranes in ACD. Future studies are needed to explore the therapeutic potential of down-regulating the expression of FN1 and balancing VIT deficiency., Competing Interests: Disclosure Statement J.C.S. received fees for lectures from Boehringer Ingelheim and Kinevant, all outside the present study. T.W. declares funding by the German Ministry of Research and Education. M.M.H. received fees for lectures and consultations from Acceleron, Actelion, AOP, Bayer, Janssen, MSD, and Pfizer, all outside the present study. J.F. received personal fees/speaker honoraria from AstraZeneca, outside the submitted work. M.G. received fees for lectures from Boehringer Ingelheim, participates in an adjudication board in a nintedanib clinical trial, and received a research grant from Boehringer Ingelheim. D.D.J. received fees for lectures from Boehringer Ingelheim and declares a research contract with Boehringer Ingelheim (contract number 43099358). All other authors declare no existing conflicts of interest., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Inertial measurement units (IMUs) are increasingly being used to assess knee function. The aim of the study was to record patients' activity levels and to detect new parameters for knee function in the early postoperative phase after TKA. Twenty patients (n = 20) were prospectively enrolled. Two sensors were attached to the affected leg. The data were recorded from the first day after TKA until discharge. Algorithms were developed for detecting steps, range of motion, horizontal, sitting and standing postures, as well as physical therapy. The mean number of steps increased from day 1 to discharge from 117.4 (SD ± 110.5) to 858.7 (SD ± 320.1), respectively. Patients' percentage of immobilization during daytime (6 a.m. to 8 p.m.) was 91.2% on day one and still 69.9% on the last day. Patients received daily continuous passive motion therapy (CPM) for a mean of 36.4 min (SD ± 8.2). The mean angular velocity at day 1 was 12.2 degrees per second (SD ± 4.4) and increased to 28.7 (SD ± 16.4) at discharge. This study shows that IMUs monitor patients' activity postoperatively well, and a wide range of interindividual motion patterns was observed. These sensors may allow the adjustment of physical exercise programs according to the patient's individual needs.

Purpose: X-ray phase-contrast tomography (XPCT) is a non-destructive, three-dimensional imaging modality that provides higher contrast in soft tissue than absorption-based CT and allows one to cover the cytoarchitecture from the centi- and millimeter scale down to the nanoscale. To further increase contrast and resolution of XPCT, for example, in view of addressing connectivity issues in the central nervous system (CNS), metal staining is indispensable. However, currently used protocols, for example, based on osmium and/or uranium are less suited for XPCT, due to an excessive β / δ -ratio. In this work, we explore the suitability of different staining agents for XPCT. Particularly, neodymium(III)-acetate (NdAc), which has recently been proposed as a non-toxic, non-radioactive easy to use alternative contrast agent for uranyl acetate (UAc) in electron microscopy, is investigated. Due to its vertical proximity to UAc in the periodic table, similar chemical but better suited optical properties for phase contrast can be expected., Approach: Differently stained whole eye samples of wild type mouse and tissues of the CNS are embedded into EPON epoxy resin and scanned using synchrotron as well as with laboratory radiation. Phase retrieval is performed on the projection images, followed by tomographic reconstruction, which enables a quantitative analysis based on the reconstructed electron densities. Segmentation techniques and rendering software is used to visualize structures of interest in the sample., Results: We show that staining neuronal samples with NdAc enhances contrast, in particular for laboratory scans, allowing high-resolution imaging of biological soft tissue in-house. For the example of murine retina, specifically rods and cones as well as the sclera and the Ganglion cell layer seem to be targeted by the stain. A comparison of electron density by the evaluation of histograms allowed to determine quantitative measures to describe the difference between the examined stains., Conclusion: The results suggest NdAc to be an effective stain for XPCT, with a preferential binding to anionic groups, such as phosphate and carboxyl groups at cell surfaces, targeting certain layers of the retina with a stronger selectivity compared to other staining agents. Due to the advantageous X-ray optical properties, the stain seems particularly well-suited for phase contrast, with a comparably small number density and an overall superior image quality at laboratory sources., (© 2023 The Authors.)

Objectives. As the central organ of the respiratory system, the human lung is responsible for supplying oxygen to the blood, which reaches the erythrocytes by diffusion through the alveolar walls and is then distributed throughout the body. By exploiting the difference in electron density detected by a phase shift in soft tissue, high-resolution x-ray phase-contrast computed tomography (XPCT) can resolve biological structures in a sub- μ m range, shedding new light on the three-dimensional structure of the lungs, physiological functions and pathological mechanisms. Approach. This work presents both synchrotron and laboratory XPCT results of postmortem tissue from autopsies and biopsies embedded with various preparation protocols such as precision-cut lung slices, cryogenically fixed lung tissue, as well as paraffin and alcohol fixed tissue. The selection of pathological abnormalities includes channel of Lambert, bronchus-associated lymphoid tissue and alveolar capillary dysplasia with misalignment of pulmonary veins. Subsequently, quantification and visualization approaches are presented. Main results. The overall high image quality even of in-house XPCT scans for the case of FFPE biopsies can be exploited for a wide range of pulmonary pathologies and translated to dedicated and optimized instrumentation which could be operated in clinical setting. By using synchrotron radiation, contrast can be further increased to resolve sub- μ m sized features down to the sub-cellular level. The results demonstrate that a wide range of preparation protocols including sample mounting in liquids can be used. Significance. With XPCT, poorly understood 3D structures can be identified in larger volume overview and subsequently studied in more detail at higher resolution. With the full 3D structure, the respective physiological functions of airways or vascular networks, and the different pathophysiologic mechanisms can be elucidated or at least underpinned with structural data. Moreover, synchrotron data can be used to validate laboratory protocols and provide ground truth for standardizing the method., (Creative Commons Attribution license.)