Extracellular Matrix as a Driver of Chronic Lung Diseases.

The extracellular matrix (ECM) is not just a three-dimensional scaffold that provides stable support for all cells in the lungs, but also an important component of chronic fibrotic airway, vascular, and interstitial diseases. It is a bioactive entity that is dynamically modulated during tissue homeostasis and disease, that controls structural and immune cell functions and drug responses, and that can release fragments that have biological activity and that can be used to monitor disease activity. There is a growing recognition of the importance of considering ECM changes in chronic airway, vascular, and interstitial diseases, including 1) compositional changes, 2) structural and organizational changes, and 3) mechanical changes and how these affect disease pathogenesis. As altered ECM biology is an important component of many lung diseases, disease models must incorporate this factor to fully recapitulate disease-driver pathways and to study potential novel therapeutic interventions. Although novel models are evolving that capture some or all of the elements of the altered ECM microenvironment in lung diseases, opportunities exist to more fully understand cell-ECM interactions that will help devise future therapeutic targets to restore function in chronic lung diseases. In this perspective article, we review evolving knowledge about the ECM's role in homeostasis and disease in the lung.

Stem Cells, Cell Therapies and Bioengineering in Lung Biology and Diseases 2023.

Repair and regeneration of a diseased lung using stem cells or bioengineered tissues is an exciting therapeutic approach for a variety of lung diseases and critical illnesses. Over the past decade increasing evidence from preclinical models suggests that cells, which are not normally resident in the lung can be utilized to modulate immune responses after injury, but there have been challenges in translating these promising findings to the clinic. In parallel, there has been a surge in bioengineering studies investigating the use of artificial and acellular lung matrices as scaffolds for three-dimensional lung or airway regeneration, with some recent attempts of transplantation in large animal models. The combination of these studies with those involving stem cells, induced pluripotent stem cell derivatives, and/or cell therapies is a promising and rapidly developing research area. These studies have been further paralleled by significant increases in our understanding of the molecular and cellular events by which endogenous lung stem and/or progenitor cells arise during lung development and participate in normal and pathologic remodeling after lung injury. For the 2023 Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference, scientific symposia were chosen to reflect the most cutting-edge advances in these fields. Sessions focused on the integration of "-omics" technologies with function, the influence of immune cells on regeneration, and the role of the extracellular matrix in regeneration. The necessity for basic science studies to enhance fundamental understanding of lung regeneration and to design innovative translational studies was reinforced throughout the conference.

International Society for Cell and Gene Therapy Clinical Translation Committee recommendations on mesenchymal stromal cells in graft-versus-host disease: easy manufacturing is faced with standardizing and commercialization challenges.

Mesenchymal stromal cells (MSCs) have been used in multiple clinical trials for steroid-refractory moderate-severe (grade II-IV) acute graft-versus-host disease (aGVHD) across the world over the last two decades. Despite very promising results in a variety of trials, it failed to get widespread approval by regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency. What lessons can we learn from this for future studies on MSCs and other cell therapy products? Broad heterogeneity among published trials using MSCs in aGVHD was likely the core problem. We propose a standardized approach in regards to donor-related factors, MSCs-related characteristics, as well as clinical trial design, to limit heterogeneity in trials for aGVHD and to fulfill the requirements of regulatory agencies. This approach may be expanded beyond MSCs to other Cell and Gene therapy products and trials in other diseases.

Mesenchymal stromal cells dampen trained immunity in house dust mite-primed macrophages expressing human macrophage migration inhibitory factor polymorphism.

BACKGROUND: Trained immunity results in long-term immunological memory, provoking a faster and greater immune response when innate immune cells encounter a secondary, often heterologous, stimulus. We have previously shown that house dust mite (HDM)-induced innate training is amplified in mice expressing the human macrophage migration inhibitory factor (MIF) CATT7 functional polymorphism. AIM: This study investigated the ability of mesenchymal stromal cells (MSCs) to modulate MIF-driven trained immunity both in vitro and in vivo. METHODS: Compared with wild-type mice, in vivo HDM-primed bone marrow-derived macrophages (BMDMs) from CATT7 mice expressed significantly higher levels of M1-associated genes following lipopolysaccharide stimulation ex vivo. Co-cultures of CATT7 BMDMs with MSCs suppressed this HDM-primed effect, with tumor necrosis factor alpha (TNF-α) being significantly decreased in a cyclooxygenase 2 (COX-2)-dependent manner. Interestingly, interleukin 6 (IL-6) was suppressed by MSCs independently of COX-2. In an in vitro training assay, MSCs significantly abrogated the enhanced production of pro-inflammatory cytokines by HDM-trained CATT7 BMDMs when co-cultured at the time of HDM stimulus on day 0, displaying their therapeutic efficacy in modulating an overzealous human MIF-dependent immune response. Utilizing an in vivo model of HDM-induced trained immunity, MSCs administered systemically on day 10 and day 11 suppressed this trained phenomenon by significantly reducing TNF-α and reducing IL-6 and C-C motif chemokine ligand 17 (CCL17) production. CONCLUSIONS: This novel study elucidates how MSCs can attenuate an MIF-driven, HDM-trained response in CATT7 mice in a model of allergic airway inflammation.

Fine-scale maps of malaria incidence to inform risk stratification in Laos.

BACKGROUND: Malaria risk maps are crucial for controlling and eliminating malaria by identifying areas of varying transmission risk. In the Greater Mekong Subregion, these maps guide interventions and resource allocation. This article focuses on analysing changes in malaria transmission and developing fine-scale risk maps using five years of routine surveillance data in Laos (2017-2021). The study employed data from 1160 geolocated health facilities in Laos, along with high-resolution environmental data. METHODS: A Bayesian geostatistical framework incorporating population data and treatment-seeking propensity was developed. The models incorporated static and dynamic factors and accounted for spatial heterogeneity. RESULTS: Results showed a significant decline in malaria cases in Laos over the five-year period and a shift in transmission patterns. While the north became malaria-free, the south experienced ongoing transmission with sporadic outbreaks. CONCLUSION: The risk maps provided insights into changing transmission patterns and supported risk stratification. These risk maps are valuable tools for malaria control in Laos, aiding resource allocation, identifying intervention gaps, and raising public awareness. The study enhances understanding of malaria transmission dynamics and facilitates evidence-based decision-making for targeted interventions in high-risk areas.

[How the implementation of a school for people with Parkinson's disease can succeed-Results of a consensus study and a formative evaluation]. / Wie die Umsetzung einer Schule für Menschen mit Parkinson-Krankheit gelingen kann ­ Ergebnisse eines Konsensusverfahrens und einer formativen Evaluation.

BACKGROUND: As the most rapidly increasing neurodegenerative disease worldwide, Parkinson's disease is highly relevant to society. Successful treatment requires active patient participation. Patient education has been successfully implemented for many chronic diseases, such as diabetes and could also provide people with Parkinson's disease with skills to manage the disease better and to participate in shared decision making. MATERIAL AND METHODS: To prepare the implementation of a concept for patient education for people with Parkinson's disease, a structured consensus study was conducted and a pilot project formatively evaluated. The structured consensus study included experts from all over Germany. It consisted of two online surveys and an online consensus conference. The formative evaluation was conducted as three focus groups. Transcripts were evaluated using content-structuring qualitative content analysis. RESULTS: From the consensus procedure 59 consented statements emerged, mainly regarding the contents of a patient school and a group size of 6-8 persons. Only two statements could not be consented. The formative evaluation detected a tendency towards a positive attitude for a digital training format and a very positive evaluation of the contents. DISCUSSION: Overall, important recommendations for a patient school can be drawn from this study. The following subjects require further investigation: format, inclusion criteria, group composition and inclusion of caregivers.

Behcet disease: A case report on the utilization of T1-weighted black blood fat-suppressed sequences for the detection of venous vasculitis.

T1-weighted black blood FS sequences may provide a useful addition to imaging protocols in detection of subtle changes in venous vasculitides and, therefore, may have an impact on treatment options.

Transarterial microembolization for the management of refractory chronic joint pain in osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative disease significantly impacting both patient quality of life and socioeconomics. Traditional treatment options, including pharmacological and surgical interventions, are often limited. Advancements in our understanding of the pathological mechanisms behind OA indicate the involvement of pathological angiogenesis. Transarterial microembolization (TAME), a minimally invasive radiological procedure, may present an innovative therapeutic approach. This review aims to consolidate current knowledge and experiences regarding TAME as a therapeutic modality for alleviating chronic joint pain associated with OA. It explores the role of TAME, focusing on its indications, patient selection, clinical outcomes, and future perspectives. Potential complications and associated risks are systematically addressed, alongside proposed strategies for risk mitigation and effective management.The presented patient cases originate from our institution, supplemented by a thorough review of relevant literature retrieved from PubMed.TAME represents a promising therapeutic approach, providing relief from the burden of joint diseases and substantially enhancing patient quality of life. Clinical outcomes emphasize the efficacy and safety of TAME in mitigating pain and improving functional capabilities in patients with chronic joint pain associated with OA. With mounting evidence of its therapeutic benefits and applicability to numerous joint-related pathologies, TAME offers a valuable addition to the arsenal of treatments for these conditions. · TAME is an innovative therapy for treating chronic joint pain related to OA.. · TAME is a technically challenging minimally invasive intervention requiring a high level of expertise.. · Understanding the challenges and complications of TAME can reduce risk and enhance procedural outcomes.. · Wilms LM, Jannusch K, Weiss D et al. Transarterial microembolization for the management of refractory chronic joint pain in osteoarthritis. Fortschr Röntgenstr 2024; DOI 10.1055/a-2288-5743.

Reproducibility and across-site transferability of an improved deep learning approach for aneurysm detection and segmentation in time-of-flight MR-angiograms.

This study aimed to (1) replicate a deep-learning-based model for cerebral aneurysm segmentation in TOF-MRAs, (2) improve the approach by testing various fully automatic pre-processing pipelines, and (3) rigorously validate the model's transferability on independent, external test-datasets. A convolutional neural network was trained on 235 TOF-MRAs acquired on local scanners from a single vendor to segment intracranial aneurysms. Different pre-processing pipelines including bias field correction, resampling, cropping and intensity-normalization were compared regarding their effect on model performance. The models were tested on independent, external same-vendor and other-vendor test-datasets, each comprised of 70 TOF-MRAs, including patients with and without aneurysms. The best-performing model achieved excellent results on the external same-vendor test-dataset, surpassing the results of the previous publication with an improved sensitivity (0.97 vs. ~ 0.86), a higher Dice score coefficient (DSC, 0.60 ± 0.25 vs. 0.53 ± 0.31), and an improved false-positive rate (0.87 ± 1.35 vs. ~ 2.7 FPs/case). The model further showed excellent performance in the external other-vendor test-datasets (DSC 0.65 ± 0.26; sensitivity 0.92, 0.96 ± 2.38 FPs/case). Specificity was 0.38 and 0.53, respectively. Raising the voxel-size from 0.5 × 0.5×0.5 mm to 1 × 1×1 mm reduced the false-positive rate seven-fold. This study successfully replicated core principles of a previous approach for detecting and segmenting cerebral aneurysms in TOF-MRAs with a robust, fully automatable pre-processing pipeline. The model demonstrated robust transferability on two independent external datasets using TOF-MRAs from the same scanner vendor as the training dataset and from other vendors. These findings are very encouraging regarding the clinical application of such an approach.

Socioeconomic, Demographic, and Environmental Factors May Inform Malaria Intervention Prioritization in Urban Nigeria.

Urban population growth in Nigeria may exceed the availability of affordable housing and basic services, resulting in living conditions conducive to vector breeding and heterogeneous malaria transmission. Understanding the link between community-level factors and urban malaria transmission informs targeted interventions. We analyzed Demographic and Health Survey Program cluster-level data, alongside geospatial covariates, to describe variations in malaria prevalence in children under 5 years of age. Univariate and multivariable models explored the relationship between malaria test positivity rates at the cluster level and community-level factors. Generally, malaria test positivity rates in urban areas are low and declining. The factors that best predicted malaria test positivity rates within a multivariable model were post-primary education, wealth quintiles, population density, access to improved housing, child fever treatment-seeking, precipitation, and enhanced vegetation index. Malaria transmission in urban areas will likely be reduced by addressing socioeconomic and environmental factors that promote exposure to disease vectors. Enhanced regional surveillance systems in Nigeria can provide detailed data to further refine our understanding of these factors in relation to malaria transmission.

Prognostic potential of integrated morphologic and metabolic parameters of pre-therapeutic [18F]FDG-PET/CT regarding progression-free survival (PFS) and overall survival (OS) in NSCLC-patients.

PURPOSE: This study aimed to evaluate the prognostic potential of pre-therapeutic [18F]FDG-PET/CT variables regarding prediction of progression-free survival (PFS) and overall survival (OS) in NSCLC-patients. METHOD: NSCLC-patients who underwent pre-therapeutic [18F]FDG-PET/CT were retrospectively analyzed. The following imaging features were collected from the primary tumor: tumor size, tumor density, central necrosis, spicules and SUVmax. For standardization, an indexSUVmax was calculated (SUVmax primary tumor/SUVmax liver). Descriptive statistics and correlations of survival time analyses for PFS and OS were calculated using the Kaplan-Meier method and Cox regression including a hazard ratio (HR). A value of p < 0.05 was set as statistically significant. The 95%-confidence intervals (CI) were calculated. The median follow-up time was 63 (IQR 27-106) months. RESULTS: This study included a total of 82 patients (25 women, 57 men; mean age: 66 ± 9 years). IndexSUVmax (PFS: HR = 1.0, CI: 1.0-1.1, p = 0.49; OS: HR = 1.0, CI: 0.9-1.2, p = 0.41), tumor size (PFS: HR = 1.0, CI: 0.9-1.0, p = 0.08; OS: HR = 1.0, CI: 0.9-1.0, p = 0.07), tumor density (PFS: HR = 0.9, CI: 0.6-1.4, p = 0.73; OS: HR = 0.3; CI: 0.1-1.1; p = 0.07), central necrosis (PFS: HR = 1.0, CI: 0.6-1.8, p = 0.98; OS: HR = 0.6, CI: 0.2-1.9, p = 0.40) and spicules (PFS: HR = 1.0, CI: 0.6-1.9, p = 0.91; OS: HR = 1.3, CI: 0.4-3.7, p = 0.65) did not significantly affect PFS and OS in the study population. An optimal threshold value for the indexSUVmax was determined by ROC analysis and Youden's index. There was no significant difference in PFS with an indexSUVmax-threshold of 3.8 (13 vs. 27 months; p = 0.45) and in OS with an indexSUVmax-threshold of 4.0 (113 vs. 106 months; p = 0.40). CONCLUSIONS: SUVmax and morphologic parameters from pre-therapeutic [18F]FDG-PET/CT were not able to predict PFS and OS in NSCLC-patients.

Identification of tyrosine brominated extracellular matrix proteins in normal and fibrotic lung tissues.

Peroxidasin (PXDN) is a secreted heme peroxidase that catalyzes the oxidative crosslinking of collagen IV within the extracellular matrix (ECM) via intermediate hypobromous acid (HOBr) synthesis from hydrogen peroxide and bromide, but recent findings have also suggested alternative ECM protein modifications by PXDN, including incorporation of bromide into tyrosine residues. In this work, we sought to identify the major target proteins for tyrosine bromination by HOBr or by PXDN-mediated oxidation in ECM from mouse teratocarcinoma PFHR9 cells. We detected 61 bromotyrosine (BrY)-containing peptides representing 23 proteins in HOBr-modified ECM from PFHR9 cells, among which laminins displayed the most prominent bromotyrosine incorporation. Moreover, we also found that laminin α1, laminin ß1, and tubulointerstitial nephritis antigen-like (TINAGL1) contained BrY in untreated PFHR9 cells, which depended on PXDN. We extended these analyses to lung tissues from both healthy mice and mice with experimental lung fibrosis, and in lung tissues obtained from human subjects. Analysis of ECM-enriched mouse lung tissue extracts showed that 83 ECM proteins were elevated in bleomycin-induced fibrosis, which included various collagens and laminins, and PXDN. Similarly, mRNA and protein expression of PXDN and laminin α/ß1 were enhanced in fibrotic mouse lung tissues, and also in mouse bone-marrow-derived macrophages or human fibroblasts stimulated with transforming growth factor ß1, a profibrotic growth factor. We identified 11 BrY-containing ECM proteins, including collagen IV α2, collagen VI α1, TINAGL1, and various laminins, in both healthy and mouse fibrotic lung tissues, although the relative extent of tyrosine bromination of laminins was not significantly increased during fibrosis. Finally, we also identified 7 BrY-containing ECM proteins in human lung tissues, again including collagen IV α2, collagen VI α1, and TINAGL1. Altogether, this work demonstrates the presence of several bromotyrosine-modified ECM proteins, likely involving PXDN, even in normal lung tissues, suggesting a potential biological function for these modifications.

Safety and efficacy of coated flow diverters in the treatment of ruptured intracranial aneurysms: a retrospective multicenter study.

BACKGROUND: This multicenter study evaluated the safety and efficacy of coated flow diverters (cFDs) for the treatment of ruptured intracranial aneurysms. METHODS: Consecutive patients treated with different cFDs for ruptured aneurysms under tirofiban at eight neurovascular centers between 2016 and 2023 were retrospectively analyzed. The majority of patients were loaded with dual antiplatelet therapy after the treatment. Aneurysm occlusion was determined using the O'Kelly-Marotta (OKM) grading scale. Primary outcome measures were major procedural complications and aneurysmal rebleeding during hospitalization. RESULTS: The study included 60 aneurysms (posterior circulation: 28 (47%)) with a mean size of 5.8±4.7 mm. Aneurysm morphology was saccular in 28 (47%), blister-like in 12 (20%), dissecting in 13 (22%), and fusiform in 7 (12%). Technical success was 100% with a mean of 1.1 cFDs implanted per aneurysm. Adjunctive coiling was performed in 11 (18%) aneurysms. Immediate contrast retention was observed in 45 (75%) aneurysms. There was 1 (2%) major procedural complication (a major stroke, eventually leading to death) and no aneurysmal rebleeding. A good outcome (modified Rankin Scale 0-2) was achieved in 40 (67%) patients. At a mean follow-up of 6 months, 27/34 (79%) aneurysms were completely occluded (OKM D), 3/34 (9%) had an entry remnant (OKM C), and 4/34 (12%) had residual filling (OKM A or B). There was 1 (3%) severe in-stent stenosis during follow-up that was treated with balloon angioplasty. CONCLUSIONS: Treatment of ruptured aneurysms with cFDs was reasonably safe and efficient and thus represents a valid treatment option, especially for complex cases.

Human movement and environmental barriers shape the emergence of dengue.

Understanding how emerging infectious diseases spread within and between countries is essential to contain future pandemics. Spread to new areas requires connectivity between one or more sources and a suitable local environment, but how these two factors interact at different stages of disease emergence remains largely unknown. Further, no analytical framework exists to examine their roles. Here we develop a dynamic modelling approach for infectious diseases that explicitly models both connectivity via human movement and environmental suitability interactions. We apply it to better understand recently observed (1995-2019) patterns as well as predict past unobserved (1983-2000) and future (2020-2039) spread of dengue in Mexico and Brazil. We find that these models can accurately reconstruct long-term spread pathways, determine historical origins, and identify specific routes of invasion. We find early dengue invasion is more heavily influenced by environmental factors, resulting in patchy non-contiguous spread, while short and long-distance connectivity becomes more important in later stages. Our results have immediate practical applications for forecasting and containing the spread of dengue and emergence of new serotypes. Given current and future trends in human mobility, climate, and zoonotic spillover, understanding the interplay between connectivity and environmental suitability will be increasingly necessary to contain emerging and re-emerging pathogens.

The Impact of Pseudomonas aeruginosa Infection in Adult Cystic Fibrosis Patients-A Single Polish Centre Study.

BACKGROUND: Pseudomonas aeruginosa (PA) is one of the most predominant pathogens of lung infections, often causing exacerbations in adult patients with cystic fibrosis (CF). MATERIALS AND METHODS: Microbiological characterization of 74 PA isolates and to evaluate the correlations between the bacterial features and 44 adult Polish CF cohort clinical parameters. RESULTS: The most common variant in the CF transmembrane conductance regulator (CFTR) gene was F508del (76.3%), followed by 3849+10kbC>T (26.3%). A total of 39.4% of the PA isolates showed multiple resistances. In patients with parameters pointing to a decline in lung function, there was a statistically significant moderate correlation with ß-lactam resistance and a weak correlation between hospital frequency and colistin resistance. The mucoidity did not correlate with the biofilm formation ability, which showed 41.9% of the isolates. Proteolytic activity, observed in 60.8% of the clinical isolates, was weakly associated with motility detected in 78.4% of the strains. The genetic profiles of the PA were highly heterogeneous, and a weak positive correlation was established between cluster group and biofilm formation. CONCLUSION: The findings suggest that there is a high variety in P. aeruginosa populations in adult CF patients. There is a need to monitor PA strains in groups of patients with cystic fibrosis, in particular, in terms of the occurrence of antibiotic resistance related to a decline in lung function.