Project description:Despite the prevalence of inhalation therapy in the treatment of pediatric respiratory disorders, most prominently asthma, the fraction of inhaled drugs reaching the lungs for maximal efficacy remains adversely low. By and large drug delivery devices and their inhalation guidelines are typically derived from adult studies with child dosages adapted according to body weight. While it has long been recognized that physiological (e.g. airway sizes, breathing maneuvers) and physical transport (e.g. aerosol dynamics) characteristics are critical in governing deposition outcomes, such knowledge has yet to be extensively adapted to younger populations. Motivated by such shortcomings, the present work leverages in a first step in silico computational fluid dynamics (CFD) to explore opportunities for augmenting aerosol deposition in children based on respiratory physiological and physical transport determinants. Using an idealized, anatomically-faithful upper airway geometry, airflow and aerosol motion are simulated as a function of age, spanning a five year old to an adult. Breathing conditions mimic realistic age-specific inhalation maneuvers representative of Dry Powder Inhalers (DPI) and nebulizer inhalation. Our findings point to the existence of a single dimensionless curve governing deposition in the conductive airways via the dimensionless Stokes number (Stk). Most significantly, we uncover the existence of a distinct deposition peak irrespective of age. For the DPI simulations, this peak (∼ 80%) occurs at Stk ≈ 0.06 whereas for nebulizer simulations, the corresponding peak (∼ 45%) occurs in the range of Stk between 0.03-0.04. Such dimensionless findings hence translate to an optimal window of micron-sized aerosols that evolves with age and varies with inhalation device. The existence of such deposition optima advocates revisiting design guidelines for optimizing deposition outcomes in pediatric inhalation therapy.
Project description:Aerosol and pollutants, in form of particulates 5-8 μm in main size face every day our respiratory system as natural suspension in air or forced to be inhaled as a coadjutant in a medical therapy for respiratory diseases. This inhalation happens in children to elderly, women and men, healthy or sick and disable people. In this paper we analyzed the inhalation of aerosol in conditions assimilable to the thermal therapy. We use a computational fluid dynamic 3D model to compute and visualize the trajectories of aerosol (3-7-10-25 µm) down to the sixth generation of bronchi, in a steady and dynamic condition (7 µm) set as breath cycle at rest. Results, compared to a set of milestone experimental studies published in literature, allow the comprehension of particles behavior during the inhalation from mouth to bronchi sixth generation, the visualization of jet at larynx constriction and vortices, in an averaged characteristic rigorous geometrical model including tracheal rings. Results on trajectories and deposition show the importance of the including transient physiological breath cycle on aerosol deposition analyses. Numerical and graphical results, may enable the design of medical devices and protocols to make the inhalations more effective in all the users' population.
Project description:We present the Biological Structure Model Archive (BSM-Arc, https://bsma.pdbj.org), which aims to collect raw data obtained via in silico methods related to structural biology, such as computationally modeled 3D structures and molecular dynamics trajectories. Since BSM-Arc does not enforce a specific data format for the raw data, depositors are free to upload their data without any prior conversion. Besides uploading raw data, BSM-Arc enables depositors to annotate their data with additional explanations and figures. Furthermore, via our WebGL-based molecular viewer Molmil, it is possible to recreate 3D scenes as shown in the corresponding scientific article in an interactive manner. To submit a new entry, depositors require an ORCID ID to login, and to finally publish the data, an accompanying peer-reviewed paper describing the work must be associated with the entry. Submitting their data enables researchers to not only have an external backup but also provide an opportunity to promote their work via an interactive platform and to provide third-party researchers access to their raw data.
Project description:Aerodynamic forces provide the primary means of distributing aerosol medications within the lungs. Partial airway obstructions can limit both air flow and aerosol penetration into diseased zones. We hypothesize that low surface tension additives may help to disperse aerosol medications after deposition in the airways, improving dose uniformity and drug delivery to underventilated regions. To test this, we performed a pilot scintigraphy study of surfactant and saline deposition and postdeposition dispersion.Because inhaled antibiotics for cystic fibrosis provide an example of where self-dispersing medications may be useful, we administered calfactant and saline aerosols with added Technetium 99m sulfur colloid (Tc-SC; 100?nm filtered) on different days in randomized order to eight cystic fibrosis (CF) subjects (average FEV(1)%, p=85 ± 12%). Nebulized delivery was matched (similar aerosol sizes and volume delivery rates, fixed breathing patterns). Tc-SC distribution in the lungs was imaged continuously for 30?min after delivery.Both aerosols were well tolerated. Aerosol distribution was mostly peripheral (58/42%) and initially similar for saline and surfactant. Changes in whole lung counts after 30?min were also similar. Peripheral lung activity decreased more rapidly on average with calfactant though the difference versus saline was not statistically significant. Central to peripheral count ratio decreased with saline and increased with calfactant and c/p changes approached significance (-0.05 ± 0.16 vs. 0.10 ± 0.10; p=0.07 Wilcoxon).Our results lack statistical significance, but suggest that inhaled calfactant increased peripheral clearance, due to either surfactant-based dispersion or mucociliary effects. Further studies are needed to define the potential for low surface tension carriers to improve drug delivery.
Project description:Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections.
Project description:A new inhaled aerosol vaccine using chimpanzee adenoviral vectors induces robust mucosal immunity in the lungs, including T cell, innate, and antibody responses, providing broader protection against SARS-CoV-2 variants. This strategy is superior to intramuscular mRNA vaccines and prior SARS-CoV-2 infection.
Project description:To test the hypothesis that autoimmunity induced by inhalation of aerosolized brain tissue caused outbreaks of sensory-predominant polyradiculoneuropathy among swine abattoir employees in the Midwestern United States.Mice were exposed intranasally, 5 days per week, to liquefied brain tissue. Serum from exposed mice, patients, and unaffected abattoir employees were analyzed for clinically pertinent neural autoantibodies.Patients, coworkers, and mice exposed to liquefied brain tissue had an autoantibody profile dominated by neural cation channel immunoglobulin Gs (IgGs). The most compelling link between patients and exposed mice was magnetic resonance imaging (MRI) evidence of grossly swollen spinal nerve roots. Autoantibody responses in patients and mice were dose-dependent and declined after antigen exposure ceased. Autoantibodies detected most frequently, and at high levels, bound to detergent-solubilized macromolecular complexes containing neuronal voltage-gated potassium channels ligated with a high affinity Kv1 channel antagonist, 125I-?-dendrotoxin. Exposed mice exhibited a behavioral phenotype consistent with potassium channel dysfunction recognized in drosophila with mutant ("shaker") channels: reduced sensitivity to isoflurane-induced anesthesia. Pathological and electrophysiological findings in patients supported peripheral nerve hyperexcitability over destructive axonal loss. The pain-predominant symptoms were consistent with sensory nerve hyperexcitability.Our observations establish that inhaled neural antigens readily induce neurological autoimmunity and identify voltage-gated potassium channel complexes as a major immunogen.
Project description:The Northwestern University Neuroimaging Data Archive (NUNDA), an XNAT-powered data archiving system, aims to facilitate secure data storage; centralized data management; automated, standardized data processing; and simple, intuitive data sharing. NUNDA is a federated data archive, wherein individual project owners regulate access to their data. NUNDA supports multiple methods of data import, enabling data collection in a central repository. Data in NUNDA are available by project to any authorized user, allowing coordinated data management and review across sites. With NUNDA pipelines, users capitalize on existing procedures or standardize custom routines for consistent, automated data processing. NUNDA can be integrated with other research databases to simplify data exploration and discovery. And data on NUNDA can be confidently shared for secure collaboration.
Project description:The upper airways of children undergo developmental changes around age 6, yielding differences between adult and pediatric anatomies. These differences include the cricoid ring area shape, the location of narrowest constriction, and the angle of the epiglottis, all of which are expected to alter local fluid dynamic profiles and subsequent upper airway deposition and downstream aerosol delivery of inhaled therapeutics. In this work, we quantify "pediatric"-like and "adult"-like geometric and fluid dynamic features of two computed tomography (CT)-scan derived models of 6-year-old upper airways in healthy subjects and compare to an idealized model. The two CT-scan models had a mixture of "adult"- and "pediatric"-like anatomic features, with Subject B exhibiting more "pediatric"-like features than Subject A, while the idealized model exhibited entirely "adult"-like features. By computational fluid-particle dynamics, these differences in anatomical features yielded distinct local fluid profiles with altered aerosol deposition between models. Notably, the idealized model better predicted deposition characteristics of Subject A, the more "adult"-like model, including the relationship between the impaction parameter, dp2Q and the fraction of deposition across a range of flow rates and particle diameters, as well as deposition of an approximate pharmaceutical particle size distribution model. Our results with even this limited dataset suggest that there are key personalized metrics that are influenced by anatomical development, which should be considered when developing pediatric inhalable therapeutics. Quantifying anatomical development and correlating to aerosol deposition has the potential for high-throughput developmental characterization and informing desired aerosol characteristics for pediatric applications.
Project description:The Protein Data Bank archive was established in 1971, and recently celebrated its 40th anniversary (Berman et al. in Structure 20:391, 2012). An analysis of interrelationships of the science, technology and community leads to further insights into how this resource evolved into one of the oldest and most widely used open-access data resources in biology.