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Intracavitary pulmonary aspergilloma is a persistent and life-threatening infection that carries a mortality rate of up to 15%. It occurs when Aspergillus species gain entry to an existing lung cavity. In the absence of definitive treatment, patients may succumb to severe complications such as massive hemoptysis, cachexia, or secondary infections. Aspergillomas often show limited response to antifungal medications, mainly due to insufficient drug concentrations within the cavities. Surgery is frequently the preferred treatment option, but it poses significant risks, and many individuals are ineligible due to underlying health issues. We present the most extensive non-surgical fungal ball cohort to date, managed using an innovative multimodal strategy that combines antifungal therapy before and after bronchoscopic debulking. This was a cross-sectional observational study. For those who cannot undergo surgery, our medical center has pioneered a multimodal approach to aspergilloma resection. This approach combines bronchoscopic endoscopy with antifungal therapy and has been applied successfully to more than 18 patients that are presented in this series. The median age of the cohort was 58 years (range: 32–73), with an equal sex distribution. The mean percent predicted FEV1 was 65.3%. The mean follow-up duration was 3.6 years (range: 0.5–10 years). The cohort receiving antifungals systematically prior to debridement showed a reduction of the pre-existing cavity (40.38 mm versus 34.02 mm, p = 0.021). Across the 18 patients during the follow-up period, 94% remained recurrence-free (defined by symptoms and radiology). Our study fills a critical knowledge gap regarding the significance of initiating antifungal treatment before bronchoscopic debulking and presents a viable approach in these cases for which there is a current unmet therapeutic need. Plain Language Summary: The use of both medical and interventional methods to treat difficult fungal masses: A collection of cases showing efficacy for patients who can't undergo surgery Intracavitary pulmonary aspergilloma is a serious and potentially deadly infection with a death rate of up to 15%. It happens when certain types of fungi invade existing lung cavities. Without proper treatment, patients may experience severe complications like heavy bleeding from the lungs, weight loss, or other infections. Traditional antifungal medications often don't work well because they can't reach high enough concentrations in the cavities. Surgery is usually the best option, but it's risky and not possible for many due to other health problems. Our study introduces a new way to treat aspergilloma without surgery. We've treated a significant number of patients using a combination of antifungal drugs and a procedure called bronchoscopic debulking. This involves removing the fungal growth using a thin tube inserted through the airways. Our research involved observing 18 patients treated this way. They were mostly middle-aged, with equal numbers of men and women. Their lung function was moderately impaired, and we followed them for an average of 3.6 years. We found that giving antifungal drugs before the debulking procedure helped reduce the size of the cavities. After treatment, almost all patients remained free of symptoms and signs of recurrence. This study highlights the importance of starting antifungal therapy before bronchoscopic debulking and offers a promising option for patients who can't have surgery. [ABSTRACT FROM AUTHOR]

Rationale: Transbronchial cryobiopsy (TBCB) for the diagnosis of interstitial lung disease (ILD) has shown promising results, but prospective studies with matched surgical lung biopsy (SLB) have yielded conflicting results. Objectives: We aimed to assess within- and between-center diagnostic agreement between TBCB and SLB at both the histopathologic and multidisciplinary discussion (MDD) levels in patients with diffuse ILD. Methods: In a multicenter prospective study, we performed matched TBCB and SLB in patients referred for SLB. After a blinded review by three pulmonary pathologists, all cases were reviewed by three independent ILD teams in an MDD. MDD was performed first with TBCB, then with SLB in a second session. Within-center and between-center diagnostic agreement was evaluated using percentages and correlation coefficients. Measurements and Main Results: Twenty patients were recruited and underwent contemporaneous TBCB and SLB. Within-center diagnostic agreement between TBCB–MDD and SLB–MDD was reached in 37 of the 60 (61.7%) paired observations, resulting in a Cohen’s κ value of 0.46 (95% confidence interval [CI], 0.29–0.63). Diagnostic agreement increased among high-confidence or definitive diagnoses on TBCB–MDD (21 of 29 [72.4%]), but not significantly, and was more likely among cases with SLB–MDD diagnoses of idiopathic pulmonary fibrosis than fibrotic hypersensitivity pneumonitis (13 of 16 [81.2%] vs. 16 of 31 [51.6%]; P = 0.047). Between-center agreement for cases was markedly higher for SLB–MDD (κ = 0.71 [95% CI, 0.52–0.89]) than TBCB–MDD (κ = 0.29 [95% CI, 0.09–0.49]). Conclusions: This study demonstrated moderate TBCB–MDD and SLB–MDD diagnostic agreement for ILD, while between-center agreement was fair for TBCB–MDD and substantial for SLB–MDD. [ABSTRACT FROM AUTHOR]

Recognition of LPS by TLR4 on immune sentinel cells such as macrophages is thought to be key to the recruitment of neutrophils to sites of infection with Gram-negative bacteria. To explore whether endothelial TLR4 plays a role in this process, we engineered and imaged mice that expressed TLR4 exclusively on endothelium (known herein as [Endothelium.sup.TLR4] mice). Local administration of LPS into tissue induced comparable neutrophil recruitment in [Endothelium.sup.TLR4] and wild-type mice. Following systemic LPS or intraperitoneal E. coli administration, most neutrophils were sequestered in the lungs of wild-type mice and did not accumulate at primary sites of infection. In contrast, [Endothelium.sup.TLR4] mice showed reduced pulmonary capillary neutrophil sequestration over the first 24 hours; as a result, they mobilized neutrophils to primary sites of infection, cleared bacteria, and resisted a dose of E. coli that killed 50% of wild-type mice in the first 48 hours. In fact, the only defect we detected in [Endothelium.sup.TLR4] mice was a failure to accumulate neutrophils in the lungs following intratracheal administration of LPS; this response required TLR4 on bone marrow--derived immune cells. Therefore, endothelial TLR4 functions as the primary intravascular sentinel system for detection of bacteria, whereas bone marrow--derived immune cells are critical for pathogen detection at barrier sites. Nonendothelial TLR4 contributes to failure to accumulate neutrophils at primary infection sites in a disseminated systemic infection., Introduction Localized infection with Gram-negative bacteria activates the local microenvironment and causes the influx of neutrophils into the afflicted tissue. The neutrophils eradicate the pathogen without eliciting any notable systemic [...]

Author(s): Yun-Yan Xiang [1]; Shuhe Wang [2]; Mingyao Liu [3, 4]; Jeremy A Hirota [5]; Jingxin Li [1, 6]; William Ju [4]; Yijun Fan [2]; Margaret M Kelly [5]; Bin [...]

It has been known for many years that neutrophils and platelets participate in the pathogenesis of severe sepsis, but the inter-relationship between these players is completely unknown. We report several cellular events that led to enhanced trapping of bacteria in blood vessels: platelet TLR4 detected TLR4 ligands in blood and induced platelet binding to adherent neutrophils. This led to robust neutrophil activation and formation of neutrophil extracellular traps (NETs). Plasma from severely septic humans also induced TLR4-dependent platelet-neutrophil interactions, leading to the production of NETs. The NETs retained their integrity under flow conditions and ensnared bacteria within the vasculature. The entire event occurred primarily in the liver sinusoids and pulmonary capillaries, where NETs have the greatest capacity for bacterial trapping. We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis., Author(s): Stephen R Clark [1, 6]; Adrienne C Ma [1, 6]; Samantha A Tavener [1]; Braedon McDonald [1]; Zahra Goodarzi [1]; Margaret M Kelly [1, 2]; Kamala D Patel [1, [...]

Key points: We have previously shown that carotid body stimulation by lysophosphatidic acid elicits a reflex stimulation of vagal efferent activity sufficient to cause bronchoconstriction in asthmatic rats.Here, we show that pathophysiological concentrations of asthma‐associated prototypical Th2 cytokines also stimulate the carotid bodies.Stimulation of the carotid bodies by these asthmakines involves a PKCε–transient receptor potential vanilloid 1 (TRPV1) signalling mechanism likely dependent on TRPV1 S502 and T704 phosphorylation sites.As the carotid bodies' oxygen sensitivity is independent of PKCε–TRPV1 signalling, systemic blockade of PKCε may provide a novel therapeutic target to reduce allergen‐induced asthmatic bronchoconstriction.Consistent with the therapeutic potential of blocking the PKCε–TRPV1 pathway, systemic delivery of a PKCε‐blocking peptide suppresses asthmatic respiratory distress in response to allergen and reduces airway hyperresponsiveness to bradykinin. The autonomic nervous system orchestrates organ‐specific, systemic and behavioural responses to inflammation. Recently, we demonstrated a vital role for lysophosphatidic acid in stimulating the primary autonomic oxygen chemoreceptors, the carotid bodies, in parasympathetic‐mediated asthmatic airway hyperresponsiveness. However, the cacophony of stimulatory factors and cellular mechanisms of carotid body activation are unknown. Therefore, we set out to determine the intracellular signalling involved in carotid body‐mediated sensing of asthmatic blood‐borne inflammatory mediators. We employed a range of in vitro and rat in situ preparations, site‐directed mutagenesis, patch‐clamp, nerve recordings and pharmacological inhibition to assess cellular signalling. We show that the carotid bodies are also sensitive to asthma‐associated prototypical Th2 cytokines which elicit sensory nerve excitation. This provides additional asthmatic ligands contributing to the previously established reflex arc resulting in efferent vagal activity and asthmatic bronchoconstriction. This novel sensing role for the carotid body is mediated by a PKCε‐dependent stimulation of transient receptor potential vanilloid 1 (TRPV1), likely via TRPV1 phosphorylation at sites T704 and S502. Importantly, carotid body oxygen sensing was unaffected by blocking either PKCε or TRPV1. Further, we demonstrate that systemic PKCε blockade reduces asthmatic respiratory distress in response to allergen and airway hyperresponsiveness. These discoveries support an inflammation‐dependent, oxygen‐independent function for the carotid body and suggest that targeting PKCε provides a novel therapeutic option to abate allergic airway disease without altering life‐saving autonomic hypoxic reflexes. Key points: We have previously shown that carotid body stimulation by lysophosphatidic acid elicits a reflex stimulation of vagal efferent activity sufficient to cause bronchoconstriction in asthmatic rats.Here, we show that pathophysiological concentrations of asthma‐associated prototypical Th2 cytokines also stimulate the carotid bodies.Stimulation of the carotid bodies by these asthmakines involves a PKCε–transient receptor potential vanilloid 1 (TRPV1) signalling mechanism likely dependent on TRPV1 S502 and T704 phosphorylation sites.As the carotid bodies' oxygen sensitivity is independent of PKCε–TRPV1 signalling, systemic blockade of PKCε may provide a novel therapeutic target to reduce allergen‐induced asthmatic bronchoconstriction.Consistent with the therapeutic potential of blocking the PKCε–TRPV1 pathway, systemic delivery of a PKCε‐blocking peptide suppresses asthmatic respiratory distress in response to allergen and reduces airway hyperresponsiveness to bradykinin. [ABSTRACT FROM AUTHOR]

Tests whether aural discrimination is significantly better when visual-spatial stimuli are paired with melodic phrases. Results suggest that the use of visual clues paired with melodies is generally an effective aid to aural discrimination among fourth-grade subjects. Recommends further research on the use of different visual stimuli. (LS)