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Pathogens (Basel, Switzerland) Apr 2024Bovine respiratory disease (BRD) is the leading cause of mortality and antimicrobial drug (AMD) use in weaned dairy heifers. Limited information is available regarding...
Bovine respiratory disease (BRD) is the leading cause of mortality and antimicrobial drug (AMD) use in weaned dairy heifers. Limited information is available regarding antimicrobial resistance (AMR) in respiratory bacteria in this population. This study determined AMR gene presence in 326 respiratory isolates (, , and ) from weaned dairy heifers using whole genome sequencing. Concordance between AMR genotype and phenotype was determined. Twenty-six AMR genes for 8 broad classes of AMD were identified. The most prevalent, medically important AMD classes used in calf rearing, to which these genes predict AMR among study isolates were tetracycline (95%), aminoglycoside (94%), sulfonamide (94%), beta-lactam (77%), phenicol (50%), and macrolide (44%). The co-occurrence of AMR genes within an isolate was common; the largest cluster of gene co-occurrence encodes AMR to phenicol, macrolide, elfamycin, β-lactam (cephalosporin, penam cephamycin), aminoglycoside, tetracycline, and sulfonamide class AMD. Concordance between genotype and phenotype varied (Matthew's Correlation Coefficient ranged from -0.57 to 1) by bacterial species, gene, and AMD tested, and was particularly poor for fluoroquinolones (no AMR genes detected) and ceftiofur (no phenotypic AMR classified while AMR genes present). These findings suggest a high genetic potential for AMR in weaned dairy heifers; preventing BRD and decreasing AMD reliance may be important in this population.
PubMed: 38668255
DOI: 10.3390/pathogens13040300 -
Respiratory Research Apr 2024Computer Aided Lung Sound Analysis (CALSA) aims to overcome limitations associated with standard lung auscultation by removing the subjective component and allowing...
BACKGROUND
Computer Aided Lung Sound Analysis (CALSA) aims to overcome limitations associated with standard lung auscultation by removing the subjective component and allowing quantification of sound characteristics. In this proof-of-concept study, a novel automated approach was evaluated in real patient data by comparing lung sound characteristics to structural and functional imaging biomarkers.
METHODS
Patients with cystic fibrosis (CF) aged > 5y were recruited in a prospective cross-sectional study. CT scans were analyzed by the CF-CT scoring method and Functional Respiratory Imaging (FRI). A digital stethoscope was used to record lung sounds at six chest locations. Following sound characteristics were determined: expiration-to-inspiration (E/I) signal power ratios within different frequency ranges, number of crackles per respiratory phase and wheeze parameters. Linear mixed-effects models were computed to relate CALSA parameters to imaging biomarkers on a lobar level.
RESULTS
222 recordings from 25 CF patients were included. Significant associations were found between E/I ratios and structural abnormalities, of which the ratio between 200 and 400 Hz appeared to be most clinically relevant due to its relation with bronchiectasis, mucus plugging, bronchial wall thickening and air trapping on CT. The number of crackles was also associated with multiple structural abnormalities as well as regional airway resistance determined by FRI. Wheeze parameters were not considered in the statistical analysis, since wheezing was detected in only one recording.
CONCLUSIONS
The present study is the first to investigate associations between auscultatory findings and imaging biomarkers, which are considered the gold standard to evaluate the respiratory system. Despite the exploratory nature of this study, the results showed various meaningful associations that highlight the potential value of automated CALSA as a novel non-invasive outcome measure in future research and clinical practice.
Topics: Humans; Cross-Sectional Studies; Male; Female; Respiratory Sounds; Prospective Studies; Adult; Cystic Fibrosis; Young Adult; Biomarkers; Adolescent; Auscultation; Tomography, X-Ray Computed; Lung; Child; Proof of Concept Study; Diagnosis, Computer-Assisted; Middle Aged
PubMed: 38658980
DOI: 10.1186/s12931-024-02810-5 -
MBio Jun 2024The airway milieu of individuals with muco-obstructive airway diseases (MADs) is defined by the accumulation of dehydrated mucus due to hyperabsorption of airway surface...
UNLABELLED
The airway milieu of individuals with muco-obstructive airway diseases (MADs) is defined by the accumulation of dehydrated mucus due to hyperabsorption of airway surface liquid and defective mucociliary clearance. Pathological mucus becomes progressively more viscous with age and disease severity due to the concentration and overproduction of mucin and accumulation of host-derived extracellular DNA (eDNA). Respiratory mucus of MADs provides a niche for recurrent and persistent colonization by respiratory pathogens, including , which is responsible for the majority of morbidity and mortality in MADs. Despite high concentration inhaled antibiotic therapies and the absence of antibiotic resistance, antipseudomonal treatment failure in MADs remains a significant clinical challenge. Understanding the drivers of antibiotic tolerance is essential for developing more effective treatments that eradicate persistent infections. The complex and dynamic environment of diseased airways makes it difficult to model antibiotic efficacy . We aimed to understand how mucin and eDNA concentrations, the two dominant polymers in respiratory mucus, alter the antibiotic tolerance of . Our results demonstrate that polymer concentration and molecular weight affect survival post antibiotic challenge. Polymer-driven antibiotic tolerance was not explicitly associated with reduced antibiotic diffusion. Lastly, we established a robust and standardized model for recapitulating the antibiotic tolerance of observed in expectorated sputum across age, underlying MAD etiology, and disease severity, which revealed the inherent variability in intrinsic antibiotic tolerance of host-evolved populations.
IMPORTANCE
Antibiotic treatment failure in chronic lung infections is associated with increased morbidity and mortality, illustrating the clinical challenge of bacterial infection control. Understanding the underlying infection environment, as well as the host and bacterial factors driving antibiotic tolerance and the ability to accurately recapitulate these factors , is crucial for improving antibiotic treatment outcomes. Here, we demonstrate that increasing concentration and molecular weight of mucin and host eDNA drive increased antibiotic tolerance to tobramycin. Through systematic testing and modeling, we identified a biologically relevant condition that recapitulates antibiotic tolerance observed in treated sputum. Ultimately, this study revealed a dominant effect of evolved bacterial populations in defining inter-subject antibiotic tolerance and establishes a robust and translatable model for therapeutic development.
Topics: Pseudomonas aeruginosa; Anti-Bacterial Agents; Pseudomonas Infections; Mucus; Humans; Mucins; Drug Resistance, Bacterial; Polymers; Persistent Infection; Lung; Respiratory Tract Infections; Adaptation, Physiological
PubMed: 38651896
DOI: 10.1128/mbio.03451-23 -
Communications Biology Apr 2024The ongoing evolution of SARS-CoV-2 to evade vaccines and therapeutics underlines the need for innovative therapies with high genetic barriers to resistance. Therefore,...
The ongoing evolution of SARS-CoV-2 to evade vaccines and therapeutics underlines the need for innovative therapies with high genetic barriers to resistance. Therefore, there is pronounced interest in identifying new pharmacological targets in the SARS-CoV-2 viral life cycle. The small molecule PAV-104, identified through a cell-free protein synthesis and assembly screen, was recently shown to target host protein assembly machinery in a manner specific to viral assembly. In this study, we investigate the capacity of PAV-104 to inhibit SARS-CoV-2 replication in human airway epithelial cells (AECs). We show that PAV-104 inhibits >99% of infection with diverse SARS-CoV-2 variants in immortalized AECs, and in primary human AECs cultured at the air-liquid interface (ALI) to represent the lung microenvironment in vivo. Our data demonstrate that PAV-104 inhibits SARS-CoV-2 production without affecting viral entry, mRNA transcription, or protein synthesis. PAV-104 interacts with SARS-CoV-2 nucleocapsid (N) and interferes with its oligomerization, blocking particle assembly. Transcriptomic analysis reveals that PAV-104 reverses SARS-CoV-2 induction of the type-I interferon response and the maturation of nucleoprotein signaling pathway known to support coronavirus replication. Our findings suggest that PAV-104 is a promising therapeutic candidate for COVID-19 with a mechanism of action that is distinct from existing clinical management approaches.
Topics: Humans; SARS-CoV-2; Virus Replication; Epithelial Cells; Antiviral Agents; Virus Assembly; COVID-19; COVID-19 Drug Treatment
PubMed: 38649430
DOI: 10.1038/s42003-024-06130-8 -
The ISME Journal Jan 2024Pseudomonas aeruginosa is a cause of chronic respiratory tract infections in people with cystic fibrosis (CF), non-CF bronchiectasis, and chronic obstructive pulmonary...
Pseudomonas aeruginosa is a cause of chronic respiratory tract infections in people with cystic fibrosis (CF), non-CF bronchiectasis, and chronic obstructive pulmonary disease. Prolonged infection allows the accumulation of mutations and horizontal gene transfer, increasing the likelihood of adaptive phenotypic traits. Adaptation is proposed to arise first in bacterial populations colonizing upper airway environments. Here, we model this process using an experimental evolution approach. Pseudomonas aeruginosa PAO1, which is not airway adapted, was serially passaged, separately, in media chemically reflective of upper or lower airway environments. To explore whether the CF environment selects for unique traits, we separately passaged PAO1 in airway-mimicking media with or without CF-specific factors. Our findings demonstrated that all airway environments-sinus and lungs, under CF and non-CF conditions-selected for loss of twitching motility, increased resistance to multiple antibiotic classes, and a hyper-biofilm phenotype. These traits conferred increased airway colonization potential in an in vivo model. CF-like conditions exerted stronger selective pressures, leading to emergence of more pronounced phenotypes. Loss of twitching was associated with mutations in type IV pili genes. Type IV pili mediate surface attachment, twitching, and induction of cAMP signalling. We additionally identified multiple evolutionary routes to increased biofilm formation involving regulation of cyclic-di-GMP signalling. These included the loss of function mutations in bifA and dipA phosphodiesterase genes and activating mutations in the siaA phosphatase. These data highlight that airway environments select for traits associated with sessile lifestyles and suggest upper airway niches support emergence of phenotypes that promote establishment of lung infection.
Topics: Pseudomonas aeruginosa; Pseudomonas Infections; Adaptation, Physiological; Biofilms; Animals; Lung; Fimbriae, Bacterial; Second Messenger Systems; Cystic Fibrosis; Mice; Humans; Anti-Bacterial Agents; Cyclic GMP; Mutation; Phenotype
PubMed: 38647527
DOI: 10.1093/ismejo/wrae065 -
Apneustic anesthesia ventilation improves pulmonary function in anesthetized bottlenose dolphins ().Frontiers in Veterinary Science 2024Use of mechanical ventilation during general anesthesia is a necessary practice in the anesthetization of small cetaceans as spontaneous ventilation fails to provide...
INTRODUCTION
Use of mechanical ventilation during general anesthesia is a necessary practice in the anesthetization of small cetaceans as spontaneous ventilation fails to provide adequate gas exchange. Currently available methods of ventilation do not account for the intermittent breathing strategy of representative species within this infraorder of fully aquatic mammals and may have a significant effect on cardiac and respiratory physiology.
METHODS
To understand the impact of mechanical ventilation on cardiopulmonary function in one small species of cetacean, the bottlenose dolphin (), we compared controlled mechanical ventilation (CMV) to a novel ventilation method known as apneustic anesthesia ventilation (AAV). AAV simulates the normal inspiratory breath-hold pattern of dolphins. Ten anesthetic procedures (dental procedure, = 9; bronchoscopy, = 2) were performed on nine dolphins (age range: 10-42 years; mean = 32 years; median = 37 years; female = 3, 40%; male = 6, 60%). In a cross-over study design, dolphins were instrumented and randomly assigned to AAV or CMV as the initial mode of ventilation, then switched to the alternate mode. Baseline cardiopulmonary data were collected and again after 30 min on each mode of ventilation. Cardiac index, stroke volume index, systemic vascular resistance, alveolar dead space, alveolar-arterial oxygen tension gradient, arterial oxygen content, oxygen delivery index, and dynamic respiratory system compliance index were calculated at each of the four time points.
RESULTS
During AAV, dolphins had higher arterial oxygen tension, higher mean airway pressure, reduced alveolar dead space ventilation and lower alveolar-arterial oxygen difference. Cardiovascular performance was not statistically different between the two modes.
DISCUSSION
Our study suggests AAV, which more closely resembles the conscious intermittent respiratory pattern phenotype of dolphins, improves ventilation and pulmonary function in the anesthetized dolphin. Future studies should evaluate the cardiopulmonary effects of neutral buoyancy and cardiopulmonary sparing drug protocols to reduce the need for hemodynamic support of current protocols.
PubMed: 38645641
DOI: 10.3389/fvets.2024.1287478 -
Academic Radiology Apr 2024It remains difficult to predict longitudinal outcomes in long-COVID, even with chest CT and functional MRI. Xe MRI reflects airway dysfunction, measured using...
RATIONALE AND OBJECTIVES
It remains difficult to predict longitudinal outcomes in long-COVID, even with chest CT and functional MRI. Xe MRI reflects airway dysfunction, measured using ventilation defect percent (VDP) and in long-COVID patients, MRI VDP was abnormal, suggestive of airways disease. While MRI VDP and quality-of-life improved 15-month post-COVID infection, both remained abnormal. To better understand the relationship of airways disease and quality-of-life improvements in patients with long-COVID, we extracted Xe ventilation MRI textures and generated machine-learning models in an effort to predict improved quality-of-life, 15-month post-infection.
MATERIALS AND METHODS
Long-COVID patients provided written-informed consent to 3-month and 15-month post-infection visits. Pyradiomics was used to extract Xe ventilation MRI texture features, which were ranked using a Random-Forest classifier. Top-ranking features were used in classification models to dichotomize patients based on St. George's Respiratory Questionnaire (SGRQ) score improvement greater than the minimal-clinically-important-difference (MCID). Classification performance was evaluated using the area under the receiver-operator-characteristic-curve (AUC), sensitivity, and specificity.
RESULTS
120 texture features were extracted from Xe ventilation MRI in 44 long-COVID participants (54 ± 14 years), including 30 (52 ± 12 years) with ΔSGRQ≥MCID and 14 (58 ± 18 years) with ΔSGRQ
airways resistance (P < .05), forced-vital-capacity (ρ = .37, P = .01) and diffusing-capacity for carbon-monoxide (ρ = .39, P = .03). CONCLUSION
A machine learning model exclusively trained on Xe MRI ventilation textures explained improved SGRQ-scores 12 months later, and outperformed clinical models. Their unique spatial-intensity information helps build our understanding about long-COVID airway dysfunction.
PubMed: 38637239
DOI: 10.1016/j.acra.2024.03.014 -
European Journal of Cell Biology Jun 2024Airway epithelial cells form a physical barrier against inhaled pathogens and coordinate innate immune responses in the lungs. Bronchial cells in people with cystic...
Airway epithelial cells form a physical barrier against inhaled pathogens and coordinate innate immune responses in the lungs. Bronchial cells in people with cystic fibrosis (pwCF) are colonized by Pseudomonas aeruginosa because of the accumulation of mucus in the lower airways and an altered immune response. This leads to chronic inflammation, lung tissue damage, and accelerated decline in lung function. Thus, identifying the molecular factors involved in the host response in the airways is crucial for developing new therapeutic strategies. The septin (SEPT) cytoskeleton is involved in tissue barrier integrity and anti-infective responses. SEPT7 is critical for maintaining SEPT complexes and for sensing pathogenic microbes. In the lungs, SEPT7 may be involved in the epithelial barrier resistance to infection; however, its role in cystic fibrosis (CF) P. aeruginosa infection is unknown. This study aimed to investigate the role of SEPT7 in controlling P. aeruginosa infection in bronchial epithelial cells, particularly in CF. The study findings showed that SEPT7 encages P. aeruginosa in bronchial epithelial cells and its inhibition downregulates the expression of other SEPTs. In addition, P. aeruginosa does not regulate SEPT7 expression. Finally, we found that inhibiting SEPT7 expression in bronchial epithelial cells (BEAS-2B 16HBE14o- and primary cells) resulted in higher levels of internalized P. aeruginosa and decreased IL-6 production during infection, suggesting a crucial role of SEPT7 in the host response against this bacterium. However, these effects were not observed in the CF cells (16HBE14o-/F508del and primary cells) which may explain the persistence of infection in pwCF. The study findings suggest the modification of SEPT7 expression as a potential approach for the anti-infective control of P. aeruginosa, particularly in CF.
Topics: Pseudomonas aeruginosa; Cystic Fibrosis; Humans; Septins; Epithelial Cells; Bronchi; Pseudomonas Infections; Cell Line
PubMed: 38636185
DOI: 10.1016/j.ejcb.2024.151416 -
Journal of Cardiothoracic Surgery Apr 2024The gastric conduit is the most commonly used replacement organ for reconstruction after minimally invasive McKeown esophagectomy. Although the optimal route of gastric...
BACKGROUND
The gastric conduit is the most commonly used replacement organ for reconstruction after minimally invasive McKeown esophagectomy. Although the optimal route of gastric conduit remains controversial, the posterior mediastinal route is physiologically preferable but is not without disadvantages. Here, we report the safety and efficacy of a method of gastric conduit reconstruction via the anterior of the pulmonary hilum route.
METHODS
We have used the anterior of the pulmonary hilum route since 2021. This procedure involves pulling the gastric conduit up through a substernal tunnel between the right thoracic cavity and the abdominal cavity and passing it into the neck via the anterior of the pulmonary hilum route. In this retrospective study, we compared the clinical outcomes between 20 patients who underwent this procedure and 20 patients who underwent the posterior mediastinal route from 2021 to 2022.
RESULTS
No mortality was reported in either group. No significant differences were observed between the two groups in duration of surgery, blood loss, incidence of postoperative complications, and postoperative hospital stay. As a result of the anterior of the pulmonary hilum route, the primary tumor bed and lymph node drainage area were effectively bypassed, which facilitates postoperative adjuvant radiotherapy or chemoradiotherapy. The distance of the gastric conduit accompanying the airway was significantly shorter in the anterior of the pulmonary hilum route group.
CONCLUSIONS
Our method is considered to be a safe and useful technique for the reconstruction of gastric conduit.
Topics: Humans; Esophagectomy; Retrospective Studies; Stomach; Postoperative Complications; Mediastinum; Esophageal Neoplasms
PubMed: 38627783
DOI: 10.1186/s13019-024-02718-7 -
International Journal of Molecular... Apr 2024As a regulator of alveolo-capillary barrier integrity, Transient Receptor Potential Vanilloid 4 (TRPV4) antagonism represents a promising strategy for reducing pulmonary...
As a regulator of alveolo-capillary barrier integrity, Transient Receptor Potential Vanilloid 4 (TRPV4) antagonism represents a promising strategy for reducing pulmonary edema secondary to chemical inhalation. In an experimental model of acute lung injury induced by exposure of anesthetized swine to chlorine gas by mechanical ventilation, the dose-dependent effects of TRPV4 inhibitor GSK2798745 were evaluated. Pulmonary function and oxygenation were measured hourly; airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, and histopathology were assessed 24 h post-exposure. Exposure to 240 parts per million (ppm) chlorine gas for ≥50 min resulted in acute lung injury characterized by sustained changes in the ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration (PaO/FiO), oxygenation index, peak inspiratory pressure, dynamic lung compliance, and respiratory system resistance over 24 h. Chlorine exposure also heightened airway response to methacholine and increased wet-to-dry lung weight ratios at 24 h. Following 55-min chlorine gas exposure, GSK2798745 marginally improved PaO/FiO, but did not impact lung function, airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, or histopathology. In summary, in this swine model of chlorine gas-induced acute lung injury, GSK2798745 did not demonstrate a clinically relevant improvement of key disease endpoints.
Topics: Animals; Swine; Chlorine; TRPV Cation Channels; Acute Lung Injury; Antineoplastic Agents; Inflammation; Oxygen; Benzimidazoles; Spiro Compounds
PubMed: 38612759
DOI: 10.3390/ijms25073949