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Background: There has been a trend to shift from a 155° and 145° neck-shaft-angle (NSA) to a more "anatomical" reverse shoulder arthroplasty with less distalization and a 135° NSA. Multiple studies have shown that a 135° NSA is beneficial for motion. There are some concerns about primary implant stability with a 135° NSA. When instability is detected, increasing the tension with thicker inlays or changing the NSA to 145° are possible solutions. A retentive 135° (Ret135) inlay may be an alternative to avoiding increased distalization; however, retentive liners are widely regarded as salvage options reducing range of motion (ROM) and avoided by most surgeons. The hypothesis of this study was that a retentive 135° insert of the tested implant system may not have drawbacks for impingement-free ROM compared to a standard 145° insert (Sta145). Methods: In this computer model study, 22 computed tomographic scans (11 males/11 females) were used to create models with a constant humeral stem (Perform/Stryker) and +3 mm lateralized baseplate +36 mm glenosphere for females and +6 mm lateralized baseplate +39 mm glenosphere for males using Blueprint software (Imascap, Brest, France). A Ret135, standard 135° (Sta135), and Sta145 (+10°) insert were compared for adduction (ADD), extension (EXT), external rotation (ER), and internal rotation (IR) all with the arm at the side as well as for combined IR (CIR = EXT + IR) and combined notching relevant (CNR) ROM (EXT + ER + IR + ADD). Results: Sta135 showed significantly better ROM for ER, IR, ADD, EXT, CNR ROM, and CIR compared to Ret135 (P < .05) and significantly better EXT and ADD compared to Sta145 (P < .0001). Comparison of Ret135 and Sta145 showed equivalent ROM performance, which was slightly better but nonsignificant for ADD (P = .16), EXT (P = .31), CNR ROM (P = .7), and CIR (P = .54) in favor of Ret135. Isolated IR (P = .39) and ER (P = .32) were slightly better but nonsignificant in favor of a Sta145. Conclusion: For this implant system tested in a computer model, a 135° standard liner offers the best ROM. A 135° retentive liner maintains at least equivalent CIR and motion to prevent notching compared to a standard 145° liner. 135° retentive liners are more than salvage options and may help to prevent distalization and overtensioning by increased liner thickness.

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The Trillat procedure, initially described by Albert Trillat, is historically one of the first techniques for addressing recurrent anterior shoulder instability, incorporating fascinating biomechanical mechanisms. After lowering, medializing, and fixing the coracoid process to the glenoid neck, the subcoracoid space is reduced, the subscapularis lowered, and its line of pull changed, accentuating the function of the subscapularis as a humeral head depressor centering the glenohumeral joint. Furthermore, the conjoint tendon creates a 'seatbelt' effect, preventing anteroinferior humeral head dislocation. Even though contemporary preferences lean towards arthroscopic Bankart repair with optional remplissage, bone augmentation, and the Latarjet procedure, enduring surgical indications remain valid for the Trillat procedure, which offers joint preservation and superior outcomes in two distinct scenarios: (i) older patients with massive irreparable cuff tears and anterior recurrent instability with an intact subscapularis tendon regardless of the extent of glenoid bone loss; (ii) younger patients with instability associated shoulder joint capsule hyperlaxity without concomitant injuries (glenoid bone loss, large Hill-Sachs lesion). Complications associated with the Trillat procedure include recurrent anterior instability, potential overtightening of the coracoid, leading to pain and a significant reduction in range of motion, risk of subcoracoid impingement, and restriction of external rotation by up to 10°, a limitation that is generally well-tolerated. The Trillat procedure may be an effective alternative technique for specific indications and should remain part of the surgical armamentarium for addressing anterior shoulder instability.

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Accurate prediction of protein-ligand binding affinities is an essential challenge in structure-based drug design. Despite recent advances in data-driven methods for affinity prediction, their accuracy is still limited, partially because they only take advantage of static crystal structures while the actual binding affinities are generally determined by the thermodynamic ensembles between proteins and ligands. One effective way to approximate such a thermodynamic ensemble is to use molecular dynamics (MD) simulation. Here, an MD dataset containing 3,218 different protein-ligand complexes is curated, and Dynaformer, a graph-based deep learning model is further developed to predict the binding affinities by learning the geometric characteristics of the protein-ligand interactions from the MD trajectories. In silico experiments demonstrated that the model exhibits state-of-the-art scoring and ranking power on the CASF-2016 benchmark dataset, outperforming the methods hitherto reported. Moreover, in a virtual screening on heat shock protein 90 (HSP90) using Dynaformer, 20 candidates are identified and their binding affinities are further experimentally validated. Dynaformer displayed promising results in virtual drug screening, revealing 12 hit compounds (two are in the submicromolar range), including several novel scaffolds. Overall, these results demonstrated that the approach offer a promising avenue for accelerating the early drug discovery process.

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OBJECTIVE: The aim of the surgery was to treat an elbow instability caused by critical coronoid bone loss (CCBL), lateral ulnar collateral ligament (LUCL) insufficiency,and general hyperlaxity by performing a direct anterior coronoid bone graft (CBG) and LUCL reconstruction in the same setting. INDICATIONS: In cases with CCBL isolated ligament reconstruction harbors a high failure rate, necessitating supplementary bony procedures. The diagnosis of CCBL is confirmed through lateral radiographs and further quantified through computed tomography (CT) imaging. Objective assessment of instability is conducted with standardized arthroscopic tests. Performing an anterior approach for CBG offers distinct advantages, notably in terms of achieving precise positioning of plates and screws and providing access to the proximal radioulnar joint. CONTRAINDICATIONS: Usual contraindications to surgery, coronoid bone loss less than 40%. SURGICAL TECHNIQUE: The surgical procedure is thoroughly illustrated with a video of the operation that can be accessed online: reconstruction of the LUCL with a semitendinosus allograft, harvesting of the graft from the iliac crest, exposure of the coronoid process with a direct anterior approach, freshening up of the graft bed. Temporary fixation of the graft with a Kirschner wire. Assessment of joint congruency, stability and range of motion (ROM) prior to definitive fixation with a 2.4 mm buttress plate and screws. FOLLOW-UP: Nonsteroidal anti-inflammatory drugs (NSAID) to prevent heterotopic ossification. Elbow mobilization in pronation from day 1 with an overhead motion protocol. Removable splint for 4 weeks, free mobilization at 6 weeks, return to sport at 3 months. RESULTS: Durable elbow stability was achieved along with free ROM and high patient satisfaction.

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Causal reasoning can be considered a cornerstone of intelligent systems. Having access to an underlying causal graph comes with the promise of cause-effect estimation and the identification of efficient and safe interventions. However, learning causal representations remains a major challenge, due to the complexity of many real-world systems. Previous works on causal representation learning have mostly focused on Variational Auto-Encoders (VAEs). These methods only provide representations from a point estimate, and they are less effective at handling high dimensions. To overcome these problems, we propose a Diffusion-based Causal Representation Learning (DCRL) framework which uses diffusion-based representations for causal discovery in the latent space. DCRL provides access to both single-dimensional and infinite-dimensional latent codes, which encode different levels of information. In a first proof of principle, we investigate the use of DCRL for causal representation learning in a weakly supervised setting. We further demonstrate experimentally that this approach performs comparably well in identifying the latent causal structure and causal variables.

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Correlation is not causation: this simple and uncontroversial statement has far-reaching implications. Defining and applying causality in biomedical research has posed significant challenges to the scientific community. In this perspective, we attempt to connect the partly disparate fields of systems biology, causal reasoning, and machine learning to inform future approaches in the field of systems biology and molecular medicine.

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Causal machine learning (ML) offers flexible, data-driven methods for predicting treatment outcomes including efficacy and toxicity, thereby supporting the assessment and safety of drugs. A key benefit of causal ML is that it allows for estimating individualized treatment effects, so that clinical decision-making can be personalized to individual patient profiles. Causal ML can be used in combination with both clinical trial data and real-world data, such as clinical registries and electronic health records, but caution is needed to avoid biased or incorrect predictions. In this Perspective, we discuss the benefits of causal ML (relative to traditional statistical or ML approaches) and outline the key components and steps. Finally, we provide recommendations for the reliable use of causal ML and effective translation into the clinic.

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Plasmacytoid dendritic cells (pDCs) produce type I interferons (IFNs) after sensing viral/bacterial RNA or DNA by toll-like receptor (TLR) 7 or TLR9, respectively. However, aberrant pDCs activation can cause adverse effects on the host and contributes to the pathogenesis of type I IFN-related autoimmune diseases. Here, we show that heparin interacts with the human pDCs-specific blood dendritic cell antigen 2 (BDCA-2) but not with related lectins such as DCIR or dectin-2. Importantly, BDCA-2-heparin interaction depends on heparin sulfation and receptor glycosylation and results in inhibition of TLR9-driven type I IFN production in primary human pDCs and the pDC-like cell line CAL-1. This inhibition is mediated by unfractionated and low-molecular-weight heparin, as well as endogenous heparin from plasma, suggesting that the local blood environment controls the production of IFN-α in pDCs. Additionally, we identified an activation-dependent soluble form of BDCA-2 (solBDCA-2) in human plasma that functions as heparin antagonist and thereby increases TLR9-driven IFN-α production in pDCs. Of importance, solBDCA-2 levels in the serum were increased in patients with scrub typhus (an acute infectious disease caused by Orientia tsutsugamushi) compared to healthy control subjects and correlated with anti-dsDNA antibodies titers. In contrast, solBDCA-2 levels in plasma from patients with bullous pemphigoid or psoriasis were reduced. In summary, this work identifies a regulatory network consisting of heparin, membrane-bound and solBDCA-2 modulating TLR9-driven IFN-α production in pDCs. This insight into pDCs function and regulation may have implications for the treatment of pDCs-related autoimmune diseases.

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Background: In reverse shoulder arthroplasty (RSA), the ideal combination of baseplate lateralization (BL), glenosphere size (GS), and glenosphere overhang (GOH) with a commonly used 145° neck shaft angle (NSA) is unclear. This is the first study evaluating correlations of body height (BH), humeral head size (HS), glenoid height (GH), and association of gender with best glenoid configurations for range of motion (ROM) maintaining anatomic lateralization (aLAT) for optimized muscle length in 145° and less distalized 135° RSA. Methods: In this computer model study, 22 computed tomographies without joint narrowing were analyzed (11 male/female). A standardized semi-inlay 145° platform stem was combined with 20 glenoid configurations (baseplate [B] 25, 25 + 3/+6 lateralized [l], 29, 29 + 3/6l combined with glenosphere 36, 36 + 2 eccentric [e], 36 + 3l, 39, 39 + 3e, 39 + 3l , 42, 42 + 4e). Abduction-adduction, flexion-extension, external rotation-internal rotation, total ROM (TROM), and total notching relevant (TNR) ROM were computed, best TROM models respecting aLAT (-1 mm to +1 mm) and HS/GH recorded. Second, the 145° models (Ascend Flex stem; Stryker, Kalamazoo, MI, USA) were converted and compared to a 135° inlay RSA (New Perform stem; Stryker, Kalamazoo, MI, USA) maintaining GOH (6.5-7 mm) and aLAT. Results: Best 145° models had eccentric glenospheres (mean BL: 3.5 mm, GOH 8.8 mm, GS 38.1 mm, distalization 23 mm). The 135° models had concentric glenospheres, mean BL 3.8 mm, GOH 6.9 mm, GS 39.7 mm, and distalization 14.1 mm. HS showed the strongest positive correlation with BL in 145° and 135° models (0.65/0.79). Despite reduced GOH in smaller females with a 135° NSA, adduction, external rotation, extension, TNR ROM, and TROM were significantly increased (P = .02, P = .005, P = .005, P = .004, P = .003), abduction however reduced (P = .02). The same trends were seen for males. Conclusion: HS is a practical measure in surgery or preoperatively, and the strong positive correlation with BL is a useful planning aid. Despite reduction of GOH, conversion to a less distalized 135° NSAinlay design is powerful to maintain and even significantly increase all components of TNR ROM (extension/external rotation/adduction) in small females with the drawback of reduced abduction which may however be compensated by scapula motion. Lateralization with a less distalized 135° RSA optimizes muscle length, may facilitate subscapularis repair, and maintains highest rigid body motion.

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Objectives. It is prescribed to determine blue-light hazard (BLH) weighted radiances, LB, for an assessment of spotlights with an angular subtense α≥11mrad. The BLH weighted irradiance, EB, can be used alternatively for smaller sources. Appropriate instruments are not common among persons commissioned with risk assessment (RA), and especially LB measurements may be challenging. Therefore, a practical BLH RA approach is proposed that is based on illuminance, Ev, pre-calculated blackbody BLH efficacies of luminous radiation, KB,vPlanck, and solid angle considerations. Methods. The practicality of this method was examined and compared against other RA approaches. Results. To ensure comparability of the applied instruments, measurements were performed close to a radiance standard, showing deviations within the lamp's expanded uncertainties (<4%), whereas the deviations were ±15% for longer distances. Focusing on a complex light-emitting diode (LED) spotlight, all detected values could be converted to LB by means of the RA methods within ±20%. Two field tests with several spotlights yielded maximum permissible exposure durations (MPED) obtained from the different RA approaches that agreed among each other within uncertainties largely below ±30%. Conclusion. The general practicality of the proposed Ev method can be concluded for a workplace BLH RA of white-light sources.

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Endogenous retroviruses (ERVs) are an integral part of the mammalian genome. The role of immune control of ERVs in general is poorly defined as is their function as anti-cancer immune targets or drivers of autoimmune disease. Here, we generate mouse-strains where Moloney-Murine Leukemia Virus tagged with GFP (ERV-GFP) infected the mouse germline. This enables us to analyze the role of genetic, epigenetic and cell intrinsic restriction factors in ERV activation and control. We identify an autoreactive B cell response against the neo-self/ERV antigen GFP as a key mechanism of ERV control. Hallmarks of this response are spontaneous ERV-GFP+ germinal center formation, elevated serum IFN-γ levels and a dependency on Age-associated B cells (ABCs) a subclass of T-bet+ memory B cells. Impairment of IgM B cell receptor-signal in nucleic-acid sensing TLR-deficient mice contributes to defective ERV control. Although ERVs are a part of the genome they break immune tolerance, induce immune surveillance against ERV-derived self-antigens and shape the host immune response.

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BACKGROUND: The popularity of team handball is increasing, with >10 million children playing this overhead throwing and collision sport with highest demands on the shoulder joint. Because of the risk of recurrent instability, the Latarjet-Patte (LP) procedure has been recommended to treat young competitive players. This is the first LP outcome study in professional handball players. METHODS: We retrospectively included 20 shoulders (18 players [17 male patients]; mean age, 22.9 years [range, 17-35 years]; minimum follow-up period, 2 years; mean follow-up period, 6.6 years) operated on by 3 expert surgeons (2011-2020) with the Walch LP technique. We documented preoperative hyperlaxity (25%, n = 5), affected throwing arm (55%, n = 11), position (backcourt, winger, and goalkeeper, 22% each; full back and pivot, 17% each), >2 dislocations prior (20%, n = 4), >10 dislocations prior (5%, n = 1), previous failed Bankart or humeral avulsion of glenohumeral ligament (HAGL) repair (10%, n = 2), and large Hill-Sachs lesions (HSLs) (20%, n = 4). Clinical and radiographic outcomes, visual analog scale score, Subjective Shoulder Value, Walch-Duplay score, Rowe score, and return-to-sport (RTS) rate were recorded. RESULTS: The RTS rate was 85% (17 of 20 shoulders); rate of RTS at the same level, 80% (16 of 20); and rate of RTS with no throwing pain, 73% (8 of 11). The time to training with a ball was 3.2 months, and the time to competition was 4.9 months. The mean Rowe score, Walch-Duplay score, and Subjective Shoulder Value were 90 points, 88 points, and 89%, respectively. Shoulder symptoms led players to give up handball in 2 cases (10%), whereas 1 player (5%) stopped playing handball for other reasons. We recorded 1 recurrent dislocation (5%) (non-throwing arm, winger, no recurrence after rehabilitation). Persistent apprehension occurred in 1 goalkeeper (5%). Residual pain was seen in 4 shoulders (20%); this was relieved by screw removal in 1. Resistant pain (throwing shoulder) was seen in 2 backcourt players (10%, 1 of whom had a large HSL) and 1 goalkeeper (5%; large HSL with >10 dislocations prior), all 3 of whom were aged > 30 years. Bone block positioning was correct (no lateral overhang) in all shoulders. At final follow-up, 1 shoulder (5%) showed mild arthritic changes (>10 dislocations, large HSL). CONCLUSION: The open LP procedure is consistent in providing shoulder stability combined with return-to-throwing performance in professional handball players with a short time to RTS and high same-level RTS rate without increasing the risk of arthritic changes. Throwing shoulders of backcourt players, large HSLs, or age > 30 years may have an increased risk of persistent symptoms.

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BACKGROUND: Bioprosthetic stentless aortic valves may degenerate over time and will require replacement. This study aimed to evaluate early- and mid-term outcomes after isolated surgical redo aortic valve replacement (redo-SAVR) and transcatheter valve-in-valve implantation (TAVI-VIV) for degenerated stentless Freestyle bioprostheses. METHODS: We reviewed records of 56 patients at a single center. Overall, 37 patients (66.1%) received TAVI-VIV and 19 (33.9%) received redo-SAVR. RESULTS: Thirty-day survival was similar in both groups (100%). One-year survival was comparable between groups (97.3% in TAVI-VIV and 100% in redo-SAVR, p = 1.0). The difference in mid-term survival after adjusting for age and EuroScore II was not significant (p = 0.41). The incidence of pacemaker implantation after TAVI-VIV was higher than after redo-SAVR (19.4% vs. 0%, p = 0.08). CONCLUSION: The 30-day and 1-year survival rates after both procedures were outstanding, irrespective of baseline characteristics. Isolated redo-SAVR should be favored in young patients, as the pacemaker implantation rate is lower. TAVI-VIV for degenerated Freestyle prosthesis can be a method of choice in elderly patients and those with high operative risk.

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Chemical short-range order (CSRO) refers to atoms of specific elements self-organising within a disordered crystalline matrix to form particular atomic neighbourhoods. CSRO is typically characterized indirectly, using volume-averaged or through projection microscopy techniques that fail to capture the three-dimensional atomistic architectures. Here, we present a machine-learning enhanced approach to break the inherent resolution limits of atom probe tomography enabling three-dimensional imaging of multiple CSROs. We showcase our approach by addressing a long-standing question encountered in body-centred-cubic Fe-Al alloys that see anomalous property changes upon heat treatment. We use it to evidence non-statistical B2-CSRO instead of the generally-expected D03-CSRO. We introduce quantitative correlations among annealing temperature, CSRO, and nano-hardness and electrical resistivity. Our approach is further validated on modified D03-CSRO detected in Fe-Ga. The proposed strategy can be generally employed to investigate short/medium/long-range ordering phenomena in different materials and help design future high-performance materials.

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In the original publication [...].

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BACKGROUND: The peroneus tertius muscle (PT) is one of the extensor muscles of the lower leg, often described as a variable separation from the extensor digitorum longus muscle (EDL). According to literature it has six different types of insertion, one of them (Olewnik Type IV) having two tendons inserting to the fifth metatarsal bone (FMTB). Morphometric data about this type of insertion is sparse, especially the relation between the two tendons, albeit the PT is suspected to contribute to stress fractures of the FMTB. Therefore, we examined this type of insertion to give detailed information on the tendons, the insertion points and the respective relations. METHODS: We examined 27 lower extremities of embalmed human bodies (12 paired, 15 single sided; 12 right and 15 left) with a distinguishable PT with two tendons inserting to the FMTB (Olewnik IV). The specimens were obtained of an undergrad dissection program, which in turn obtained them from a body donation program. After dissection of the PT and photo documentation in situ, resection and measurement of morphological properties of the tendons were performed with the PT attached to the fifth metatarsal bone. RESULTS: Results of the respective measurements yielded a wide range of variation, especially in the insertion point of the anterior tendon on the fifth metatarsal and the relation between the two tendons, but with no significant difference between sides or sex, except for the length of the posterior tendon between sex. The distance between the base of the FMTB and posterior tendon varies from 0 to 9 mm, with one outlier at 24 mm (mean = 3.9 ± 4.8 mm), the distance between the insertions from 0 to 15 mm (mean = 4.7 ± 4.7 mm), resulting in how far of the FMTB the anterior tendon reaches varying from 17 to 60 mm (mean = 39.6 ± 11.5 mm) or 22-98% (mean = 64 ± 19%). CONCLUSION: Our findings give a detailed overview of the morphological features the PTT can have, when attached with two tendons to the FMTB. Especially the varying relationship between those two insertions and varying point of the anterior insertion are of interest, as they might support its complex role in the occurrence of fractures of the fifth metatarsal by providing different amounts of torsional stress and its tendons can be used as tendon-grafts.

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PURPOSE: This phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians' choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC). PATIENTS AND METHODS: The initial randomized study design was later amended into a single-arm study, and all subsequent patients received ribociclib and ET. The primary end point was locally assessed progression-free survival (PFS). Secondary end points included overall survival (OS), clinical benefit rate (CBR), safety, compliance, and quality of life (QoL). RESULTS: A total of 43 patients received ribociclib + ET and 10 patients received ET only. Median PFS was 12.4 months [95% CI 8.7-24.4] for patients who received ribociclib + ET and 4.75 months [95% CI 1.0-10.3] for those who received ET only. Median OS was not reached for patients who received ribociclib + ET, and 28 (65.1%) patients experienced clinical benefit [95% CI 49.1-79.0]. For patients who received ribociclib + ET, grade 3-4 hematological adverse events (AEs) occurred in 25 (58.1%) patients, and grade 3-4 non-hematological AEs occurred in 17 (39.5%) patients. During the study, 15 patients died - 14 of whom due to tumor-related reasons, and one patient due to pneumonia, which was not treatment-related. CONCLUSION: The results of the AMICA study show a promising efficacy and safety of maintenance treatment with ribociclib added to ET after at least stable disease following the first metastatic chemotherapy in patients with HR+/HER2-mBC. TRIAL REGISTRATION: Anti-hormonal Therapy With Ribociclib in HR-positive/HER2- Negative Metastatic Breast Cancer (AMICA), NCT03555877, https://clinicaltrials.gov/ct2/show/NCT03555877.

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Chronic traumatic anterior shoulder instability can be defined as recurrent trauma-associated shoulder instability requiring the assessment of three anatomic lesions: a capsuloligamentous and/or labral lesion; anterior glenoid bone loss and a Hill-Sachs lesion. Surgical treatment is generally indicated. It remains controversial how risk factors should be evaluated to decide between a soft-tissue, free bone-block or Latarjet-type procedure. Patient risk factors for recurrence are age; hyperlaxity; competitive, contact and overhead sports. Trauma-related factors are soft tissue lesions and most importantly bone loss with implications for treatment. Different treatment options are discussed and compared for complications, return to sports parameters, short- and long-term outcomes and osteoarthritis. Arthroscopic Bankart and open Latarjet procedures have a serious learning curve. Osteoarthritis is associated with the number of previous dislocations as well as surgical techniques. Latarjet-type procedures have the lowest rate of dislocation recurrence and if performed correctly, do not seem to increase the risk of osteoarthritis.

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Many viruses require proteolytic activation of their envelope proteins for infectivity, and relevant host proteases provide promising drug targets. The transmembrane serine protease 2 (TMPRSS2) has been identified as a major activating protease of influenza A virus (IAV) and various coronaviruses (CoV). Increased TMPRSS2 expression has been associated with a higher risk of severe influenza infection and enhanced susceptibility to SARS-CoV-2. Here, we found that Legionella pneumophila stimulates the increased expression of TMPRSS2-mRNA in Calu-3 human airway cells. We identified flagellin as the dominant structural component inducing TMPRSS2 expression. The flagellin-induced increase was not observed at this magnitude for other virus-activating host proteases. TMPRSS2-mRNA expression was also significantly increased by LPS, Pam3Cys, and Streptococcus pneumoniae, although less pronounced. Multicycle replication of H1N1pdm and H3N2 IAV but not SARS-CoV-2 and SARS-CoV was enhanced by flagellin treatment. Our data suggest that bacteria, particularly flagellated bacteria, up-regulate the expression of TMPRSS2 in human airway cells and, thereby, may support enhanced activation and replication of IAV upon co-infections. In addition, our data indicate a physiological role of TMPRSS2 in antimicrobial host response.

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Gram-negative bacteria naturally secrete nano-sized outer membrane vesicles (OMVs), which are important mediators of communication and pathogenesis. OMV uptake by host cells activates TLR signalling via transported PAMPs. As important resident immune cells, alveolar macrophages are located at the air-tissue interface where they comprise the first line of defence against inhaled microorganisms and particles. To date, little is known about the interplay between alveolar macrophages and OMVs from pathogenic bacteria. The immune response to OMVs and underlying mechanisms are still elusive. Here, we investigated the response of primary human macrophages to bacterial vesicles (Legionella pneumophila, Klebsiella pneumoniae, Escherichia coli, Salmonella enterica, Streptococcus pneumoniae) and observed comparable NF-κB activation across all tested vesicles. In contrast, we describe differential type I IFN signalling with prolonged STAT1 phosphorylation and strong Mx1 induction, blocking influenza A virus replication only for Klebsiella, E.coli and Salmonella OMVs. OMV-induced antiviral effects were less pronounced for endotoxin-free Clear coli OMVs and Polymyxin-treated OMVs. LPS stimulation could not mimic this antiviral status, while TRIF knockout abrogated it. Importantly, supernatant from OMV-treated macrophages induced an antiviral response in alveolar epithelial cells (AEC), suggesting OMV-induced intercellular communication. Finally, results were validated in an ex vivo infection model with primary human lung tissue. In conclusion, Klebsiella, E.coli and Salmonella OMVs induce antiviral immunity in macrophages via TLR4-TRIF-signaling to reduce viral replication in macrophages, AECs and lung tissue. These gram-negative bacteria induce antiviral immunity in the lung through OMVs, with a potential decisive and tremendous impact on bacterial and viral coinfection outcome. Video Abstract.

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