Management of Vestibular Schwannoma with Normal Hearing.

INTRODUCTION: This work aimed to study the management of vestibular schwannoma (VS) patients with normal hearing (NH). METHODS: A retrospective study was undertaken in a Quaternary referral center for skull base pathologies. Among 4,000 VS patients 162 met our strict audiological criteria for NH. These patients were divided into 2 management groups, wait and scan (W&S) (45/162, 25%) and operated patients (123/162, 75%), and 6 patients were included in both groups. RESULTS: Our management strategy achieved the goals for treatment of VS. First goal, all tumors were completely removed except for 2 intentional residuals. Second goal, facial nerve (FN) function preservation (House Brackmann I, II, and III) was 95.9%. Third goal, possible hearing preservation (HP) attempts occurred in (50/122) (40.9%) with an HP rate in 44% of the patients. Additionally, there were only 2 cases of postoperative complications with no CSF leakage. The prospect of HP in NH patients did not differ with respect to tumor size. However, patients with normal preoperative ABR seemed to have better chances of HP and good FN function and vice versa. HP rate was superior for the MCFA as opposed to the RS + RLA. W&S group demonstrated hearing stability in 88.9% of the patients and FN function stability of HB I in 100% of the patients. CONCLUSIONS: Surgical resection is a reasonable and definitive management option for VS with NH. Nevertheless, choosing to manage cases with observation remains an appropriate management option for NH patients. ABR might be considered as an adjuvant tool indicating better prognosis for HP.

Inhalation dosimetry of nasally inhaled respiratory aerosols in the human respiratory tract with locally remodeled conducting lungs.

Objective: Respiratory diseases are often accompanied by alterations to airway morphology. However, inhalation dosimetry data in remodeled airways are scarce due to the challenges in reconstructing diseased respiratory morphologies. This study aims to study the airway remodeling effects on the inhalation dosimetry of nasally inhaled nanoparticles in a nose-lung geometry that extends to G9 (ninth generation).Materials and methods: Statistical shape modeling was used to develop four diseased lung models with varying levels of bronchiolar dilation/constriction in the left-lower (LL) lobe (i.e. M1-M4). Respiratory airflow and particle deposition were simulated using a low Reynolds number k-ω turbulence model and a Lagrangian tracking approach.Results: Significant discrepancies were observed in the flow partitions between the left and right lungs, as well as between the lower and upper lobes of the left lung, which changed by 10-fold between the most dilated and constricted models.Much lower doses were predicted on the surface of the constricted LL bronchioles G4-G9, as well as into the peripheral airways beyond G9 of the LL lung. However, the LL lobar remodeling had little effect on the dosimetry in the nasopharynx, as well as on the total dosimetry in the nose-lung geometry (up to G9).Conclusion: It is suggested that airway remodeling may pose a higher viral infection risk to the host by redistributing the inhaled viruses to healthy lung lobes. Airway remodeling effects should also be considered in the treatment planning of inhalation therapies, not only because of the dosimetry variation from altered lung morphology but also its evolution as the disease progresses.

Trauma in northern Quebec, 2005-2014: epidemiologic features, transfers and patient outcomes.

BACKGROUND: The Inuit people residing in Nunavik, Quebec, are vulnerable to major trauma owing to environmental and social factors; however, there is no systematic data collection for trauma in Nunavik, and, apart from data regarding patients who are transferred to tertiary care centres, no data enter the Quebec trauma registry directly from Nunavik. We performed a study to characterize the epidemiologic features of trauma in Nunavik, and describe indications for transfer and outcomes of patients referred to the tertiary trauma centre. METHODS: We collected data retrospectively for all patients with trauma admitted to the Centre de santé Tulattavik de l'Ungava in Kuujjuaq from 2005 to 2014. Sociodemographic, injury and health services data were extracted. The data were analyzed in conjunction with coroners' reports on death from trauma in Nunavik. RESULTS: A total of 797 trauma cases were identified. The most common causes of injury were motor vehicle collisions (258 cases [32.4%]), falls (137 [17.2%]) and blunt assault (95 [11.9%]). One-third of patients (262 [32.9%]) were transferred to the tertiary care centre in Montréal. The incidence rate of major trauma (Injury Severity Score > 12) was 18.1 and 21.7 per 10 000 person-years in the Kuujjuaq region and the Puvirnituq region, respectively, which translates to a relative risk (RR) of 4 compared to the Quebec population. The disparity observed in trauma mortality rate was even greater, with an RR of 47.6 compared to the Quebec population. CONCLUSION: The study showed major disparity in trauma incidence and mortality rate between Nunavik and the province of Quebec. Our findings allow for a better understanding of the burden of injury and regional trauma mortality in Nunavik, and recommendations for optimization of the trauma system in this unique setting.

Audiological Evaluation of Vestibular Schwannoma Patients with Normal Hearing.

OBJECTIVE: To evaluate the audiological aspects of vestibular schwannoma (VS) patients with normal hearing. STUDY DESIGN: Retrospective study. SETTING: Quaternary referral center for skull base pathologies. PATIENTS: The records on 4,000 patients who had been diagnosed with VS between 1986 and December 2017 were retrospectively reviewed. The patients included in the study were the ones who complied with the strict audiological normality criteria, as follows: a pure tone hearing threshold (at the 6-octave-spaced frequencies from 250 to 8,000 Hz) ≤25 dBHL; a word recognition score >90%; and interaural differences ≤10 dB at each frequency. INTERVENTIONS: Auditory brainstem response (ABR) testing and radiological imaging. MAIN OUTCOME MEASURES: The incidence of normal objective hearing among VS patients, and the diagnostic utility of the ABR and the effect of tumor size and site on the response. RESULTS: The incidence of normal hearing among VS patients was 4.2%. Tinnitus and vertigo were the most common symptoms across tumor grades; 5.6% of the tumors were large and giant tumors. The ABR yielded a sensitivity of 73.6%, with a false negative rate of 26.3% using a cutoff point of 0.2 ms for interaural latency differences. CONCLUSIONS: The diagnosis of VS should not be based on audiometric thresholds alone. Alarming signs of VS should be clear to the physician in order not to miss or delay the diagnosis of the disease. The ABR is useful in the diagnosis of VS, but normal results do not exclude the occurrence of the disease in patients with normal hearing.

Survival of Nasal Tip Flap on Only the Columellar Attachment.

The nose has a robust blood supply derived from both internal and external carotid arteries. The main blood supply of the nasal tip and skin is derived primarily from the lateral nasal arteries, with a variable contribution from the columellar arteries. We present a patient with cut nose resulting from a homicidal attack in which the lower two-thirds of the nose was severed starting at the bony-cartilaginous junction of the dorsum of the nose down to the tip of the nose. The skin-cartilage flap was attached only to the columella and to the caudalmost 3 mm of the left ala nasi. The detached skin-cartilage flap was replaced and sutured anatomically, and the flap completely survived in spite of cutting of both lateral and dorsal nasal arteries.

Congenital hand anomalies in Upper Egypt.

BACKGROUND: Congenital hand anomalies are numerous and markedly variant. Their significance is attributed to the frequent occurrence and their serious social, psychological and functional impacts on patient's life. PATIENTS AND METHODS: This is a follow-up study of 64 patients with hand anomalies of variable severity. All patients were presented to Plastic Surgery Department of Sohag University Hospital in a period of 24 months. RESULTS: This study revealed that failure of differentiation and duplication deformities were the most frequent, with polydactyly was the most common anomaly encountered. The mean age of presentation was 6 years and female to male ratio was 1.46:1. Hand anomalies were either isolated, associated with other anomalies or part of a syndrome. CONCLUSION: Incidence of congenital hand anomalies in Upper Egypt is difficult to be estimated due to social and cultural concepts, lack of education, poor registration and deficient medical survey. Management of hand anomalies should be individualised, carefully planned and started as early as possible to achieve the best outcome.

Schlieren imaging and video classification of alphabet pronunciations: exploiting phonetic flows for speech recognition and speech therapy.

Speech is a highly coordinated process that requires precise control over vocal tract morphology/motion to produce intelligible sounds while simultaneously generating unique exhaled flow patterns. The schlieren imaging technique visualizes airflows with subtle density variations. It is hypothesized that speech flows captured by schlieren, when analyzed using a hybrid of convolutional neural network (CNN) and long short-term memory (LSTM) network, can recognize alphabet pronunciations, thus facilitating automatic speech recognition and speech disorder therapy. This study evaluates the feasibility of using a CNN-based video classification network to differentiate speech flows corresponding to the first four alphabets: /A/, /B/, /C/, and /D/. A schlieren optical system was developed, and the speech flows of alphabet pronunciations were recorded for two participants at an acquisition rate of 60 frames per second. A total of 640 video clips, each lasting 1 s, were utilized to train and test a hybrid CNN-LSTM network. Acoustic analyses of the recorded sounds were conducted to understand the phonetic differences among the four alphabets. The hybrid CNN-LSTM network was trained separately on four datasets of varying sizes (i.e., 20, 30, 40, 50 videos per alphabet), all achieving over 95% accuracy in classifying videos of the same participant. However, the network's performance declined when tested on speech flows from a different participant, with accuracy dropping to around 44%, indicating significant inter-participant variability in alphabet pronunciation. Retraining the network with videos from both participants improved accuracy to 93% on the second participant. Analysis of misclassified videos indicated that factors such as low video quality and disproportional head size affected accuracy. These results highlight the potential of CNN-assisted speech recognition and speech therapy using articulation flows, although challenges remain in expanding the alphabet set and participant cohort.

Delivery of Agarose-aided Sprays to the Posterior Nose for Mucosa Immunization and Short-term Protection against Infectious Respiratory Diseases.

AIM: The study aimed to deliver sprays to the posterior nose for mucosa immunization or short-term protection. BACKGROUND: Respiratory infectious diseases often enter the human body through the nose. Sars-Cov-2 virus preferentially binds to the ACE2-rich tissue cells in the nasopharynx (NP). Delivering medications to the nose, especially to the NP region, provides either a short-term protective/therapeutic layer or long-term mucosa immunization. Hydrogel-aided medications can assist film formation, prolong film life, and control drug release. However, conventional nasal sprays have failed to dispense mediations to the posterior nose, with most sprays lost in the nasal valve and front turbinate. OBJECTIVE: The objective of the study was to develop a practical delivery system targeting the posterior nose and quantify the dosimetry distribution of agarose-saline solutions in the nasal cavity. METHOD: The solution viscosities with various hydrogel concentrations (0.1-1%) were measured at different temperatures. Dripping tests on a vertical plate were conducted to understand the hydrogel concentration effects on the liquid film stability and mobility. Transparent nasal airway models were used to visualize the nasal spray deposition and liquid film translocation. RESULT: Spray dosimetry with different hydrogel concentrations and inhalation flow rates was quantified on a total and regional basis. The solution viscosity increased with decreasing temperature, particularly in the range of 60-40 oC. The liquid viscosity, nasal spray atomization, and liquid film mobility were highly sensitive to the hydrogel concentration. Liquid film translocations significantly enhanced delivered doses to the caudal turbinate and nasopharynx when the sprays were administered at 60 oC under an inhalation flow rate of 11 L/min with hydrogel concentrations no more than 0.5%. On the other hand, sprays with 1% hydrogel or administered at 40 oC would significantly compromise the delivered doses to the posterior nose. CONCLUSION: Delivering sufficient doses of hydrogel sprays to the posterior nose is feasible by leveraging the post-administration liquid film translocation.

A Supine Position and Dual-Dose Applications Enhance Spray Dosing to the Posterior Nose: Paving the Way for Mucosal Immunization.

Delivering vaccines to the posterior nose has been proposed to induce mucosal immunization. However, conventional nasal devices often fail to deliver sufficient doses to the posterior nose. This study aimed to develop a new delivery protocol that can effectively deliver sprays to the caudal turbinate and nasopharynx. High-speed imaging was used to characterize the nasal spray plumes. Three-dimensional-printed transparent nasal casts were used to visualize the spray deposition within the nasal airway, as well as the subsequent liquid film formation and translocation. Influencing variables considered included the device type, delivery mode, release angle, flow rate, head position, and dose number. Apparent liquid film translocation was observed in the nasal cavity. To deliver sprays to the posterior nose, the optimal release angle was found to be 40° for unidirectional delivery and 30° for bidirectional delivery. The flow shear was the key factor that mobilized the liquid film. Both the flow shear and the head position were important in determining the translocation distance. A supine position and dual-dose application significantly improved delivery to the nasopharynx, i.e., 31% vs. 0% with an upright position and one-dose application. It is feasible to effectively deliver medications to the posterior nose by leveraging liquid film translocation for mucosal immunization.

The relation between long latency cortical auditory evoked potentials and stuttering severity in stuttering school-age children.

BACKGROUND: Disturbances in auditory processing and feedback have been suggested to play a role in the pathogenesis of developmental stuttering. Long latency cortical auditory evoked potentials in response to non-linguistic and linguistic stimuli can be used to investigate these disturbances. There were differences between developmental stuttering patients. However, there is no solid evidence of these differences to date. OBJECTIVE: This study aims to determine whether there is a statistically significant difference in component P1-N1-P2 of long latency cortical auditory evoked potentials between stuttering school-aged children and non-stuttering children. In addition, the study aims to investigate the relationship between these potentials and objective quantitative measures of stuttering. METHOD: The study included two groups, patients and controls, consisting of 40 subjects aged 6-12 years. For the cases group, the severity of stuttering symptoms and P1-N1-P2 responses to a non-linguistic stimulus were evaluated. In addition, the P1-N1-P2 responses of the matched control group were evaluated. RESULTS: The P1-N1 responses were similar in both study groups, while P2 response was shorter in the patient group, but the difference was not statistically significant compared to the control group. N1 latency has the only statistically significant correlation with the percentage of repetitions, prolongation, and blocks. The female cases had a decreased, not statistically significant, latency than the male cases group. CONCLUSION: In contrast to the previous finding, the study revealed a non-statistically significant different P1-N1, a non-statistically significant reduced P2 response to a non-linguistic stimulus, in CWS, in as evidence for basic auditory processing. The study also revealed a significant correlation between N1 latency and proportion of the repetition symptoms.

Count- and mass-based dosimetry of MDI spray droplets with polydisperse and monodisperse size distributions.

Most previous numerical studies of inhalation drug delivery used monodisperse aerosols or quantified deposition as the ratio of deposited particle number over the total number of released particles (i.e., count-based). These practices are reasonable when the aerosols have a sufficiently narrow size range. However, spray droplets from metered-dose inhalers (MDIs) are often polydisperse with a wide size range, so using monodisperse aerosols and/or count-based deposition quantification may lead to significant errors. The objective of this study was to develop a mass-based dosimetry method and evaluate its performance in lung delivery in a mouth-lung (G9) geometry with an albuterol-CFC inhaler. The conventional practices (monodisperse and polydisperse-count-based) were also simulated for comparison purposes. The MDI actuation in the open space was studied using both high-speed imaging and LES-Lagrangian simulations. Experimentally measured spray velocities and size distribution were implemented in the computational model as boundary conditions. Good agreement was achieved between recorded and simulated spray plume evolution spatially and temporally. The polydisperse-mass-based predictions of MDI doses compared favorably with the measurements in all three regions considered (device, mouth-throat, and lung). Significant errors in MDI regional deposition were predicted using the monodisperse and count-based methods. The new polydisperse-mass-based method also predicted local deposition hot spots that were one order of magnitude higher in intensity than the two conventional methods. The results of this study highlighted that a presentative polydisperse size distribution and appropriate deposition quantification method should be applied to reliably predict the MDI drug delivery in the human respiratory tract.

Lower Inspiratory Breathing Depth Enhances Pulmonary Delivery Efficiency of ProAir Sprays.

Effective pulmonary drug delivery using a metered-dose inhaler (MDI) requires a match between the MDI sprays, the patient's breathing, and respiratory physiology. Different inhalers generate aerosols with distinct aerosol sizes and speeds, which require specific breathing coordination to achieve optimized delivery efficiency. Inability to perform the instructed breathing maneuver is one of the frequently reported issues during MDI applications; however, their effects on MDI dosimetry are unclear. The objective of this study is to systemically evaluate the effects of breathing depths on regional deposition in the respiratory tract using a ProAir-HFA inhaler. An integrated inhaler mouth-throat-lung geometry model was developed that extends to the ninth bifurcation (G9). Large-eddy simulation (LES) was used to compute the airflow dynamics due to concurrent inhalation and orifice flows. The discrete-phase Lagrangian model was used to track droplet motions. Experimental measurements of ProAir spray droplet sizes and speeds were used as initial and boundary conditions to develop the computational model for ProAir-pulmonary drug delivery. The time-varying spray plume from a ProAir-HFA inhaler into the open air was visualized using a high-speed imaging system and was further used to validate the computational model. The inhalation dosimetry of ProAir spray droplets in the respiratory tract was compared among five breathing depths on a regional, sub-regional, and local basis. The results show remarkable differences in airflow dynamics within the MDI mouthpiece and the droplet deposition distribution in the oral cavity. The inhalation depth had a positive relationship with the deposition in the mouth and a negative relationship with the deposition in the five lobes beyond G9 (small airways). The highest delivery efficiency to small airways was highest at 15 L/min and declined with an increasing inhalation depth. The drug loss inside the MDI was maximal at 45-60 L/min. Comparisons to previous experimental and numerical studies revealed a high dosimetry sensitivity to the inhaler type and patient breathing condition. Considering the appropriate inhalation waveform, spray actuation time, and spray properties (size and velocity) is essential to accurately predict inhalation dosimetry from MDIs. The results highlight the importance of personalized inhalation therapy to match the patient's breathing patterns for optimal delivery efficiencies. Further complimentary in vitro or in vivo experiments are needed to validate the enhanced pulmonary delivery at 15 L/min.

Effect of MDI Actuation Timing on Inhalation Dosimetry in a Human Respiratory Tract Model.

Accurate knowledge of the delivery of locally acting drug products, such as metered-dose inhaler (MDI) formulations, to large and small airways is essential to develop reliable in vitro/in vivo correlations (IVIVCs). However, challenges exist in modeling MDI delivery, due to the highly transient multiscale spray formation, the large variability in actuation-inhalation coordination, and the complex lung networks. The objective of this study was to develop/validate a computational MDI-releasing-delivery model and to evaluate the device actuation effects on the dose distribution with the newly developed model. An integrated MDI-mouth-lung (G9) geometry was developed. An albuterol MDI with the chlorofluorocarbon propellant was simulated with polydisperse aerosol size distribution measured by laser light scatter and aerosol discharge velocity derived from measurements taken while using a phase Doppler anemometry. The highly transient, multiscale airflow and droplet dynamics were simulated by using large eddy simulation (LES) and Lagrangian tracking with sufficiently fine computation mesh. A high-speed camera imaging of the MDI plume formation was conducted and compared with LES predictions. The aerosol discharge velocity at the MDI orifice was reversely determined to be 40 m/s based on the phase Doppler anemometry (PDA) measurements at two different locations from the mouthpiece. The LES-predicted instantaneous vortex structures and corresponding spray clouds resembled each other. There are three phases of the MDI plume evolution (discharging, dispersion, and dispensing), each with distinct features regardless of the actuation time. Good agreement was achieved between the predicted and measured doses in both the device, mouth-throat, and lung. Concerning the device-patient coordination, delayed MDI actuation increased drug deposition in the mouth and reduced drug delivery to the lung. Firing MDI before inhalation was found to increase drug loss in the device; however, it also reduced mouth-throat loss and increased lung doses in both the central and peripheral regions.

Two-way coupling and Kolmogorov scales on inhaler spray plume evolutions from Ventolin, ProAir, and Qvar.

Previous numerical studies of pulmonary drug delivery using metered-dose inhalers (MDIs) often neglected the momentum transfer from droplets to fluid. However, Kolmogorov length scales in MDI flows can be comparable to the droplet sizes in the orifice vicinity, and their interactions can modify the spray behaviors. This study aimed to evaluate the two-way coupling effects on spray plume evolutions compared to one-way coupling. The influences from the mass loading, droplet size, and inhaler type were also examined. Large-eddy simulation and Lagrangian approach were used to simulate the flow and droplet motions. Two-way coupled predictions appeared to provide significantly improved predictions of the aerosol behaviors close to the Ventolin orifice than one-way coupling. Increasing the applied MDI dose mass altered both the fluid and aerosol dynamics, notably bending the spray plume downward when applying a dose ten times larger. The droplet size played a key role in spray dynamics, with the plume being suppressed for 2-µm aerosols and enhanced for 20-µm aerosols. The Kolmogorov length scale ratio dp/η correlated well with the observed difference in spray plumes, with suppressed plumes when dp/η < 0.1 and enhanced plumes when dp/η > 0.1. For the three inhalers considered (Ventolin, ProAir, and Qvar), significant differences were predicted using two-way and one-way coupling despite the level and manifestation of these differences varied. Two-way coupling effects were significant for MDI sprays and should be considered in future numerical studies.

SARS COV-2 virus-laden droplets coughed from deep lungs: Numerical quantification in a single-path whole respiratory tract geometry.

When an infected person coughs, many virus-laden droplets will be exhaled out of the mouth. Droplets from deep lungs are especially infectious because the alveoli are the major sites of coronavirus replication. However, their exhalation fraction, size distribution, and exiting speeds are unclear. This study investigated the behavior and fate of respiratory droplets (0.1-4 µm) during coughs in a single-path respiratory tract model extending from terminal alveoli to mouth opening. An experimentally measured cough waveform was used to control the alveolar wall motions and the flow boundary conditions at lung branches from G2 to G18. The mouth opening was modeled after the image of a coughing subject captured using a high-speed camera. A well-tested k-ω turbulence model and Lagrangian particle tracking algorithm were applied to simulate cough flow evolutions and droplet dynamics under four cough depths, i.e., tidal volume ratio (TVR) = 0.13, 0.20. 0.32, and 0.42. The results show that 2-µm droplets have the highest exhalation fraction, regardless of cough depths. A nonlinear relationship exists between the droplet exhalation fraction and cough depth due to a complex deposition mechanism confounded by multiscale airway passages, multiregime flows, and drastic transient flow effects. The highest exhalation fraction is 1.6% at the normal cough depth (TVR = 0.32), with a mean exiting speed of 20 m/s. The finding that most exhaled droplets from deep lungs are 2 µm highlights the need for more effective facemasks in blocking 2-µm droplets and smaller both in infectious source control and self-protection from airborne virus-laden droplets.

Contentious Issues in Gout Management: The Story so Far.

Gout is the most common inflammatory arthritis worldwide. Although gout has been known for antiquity, many challenges still exist in gout management. It is vital to view gout as a chronic disease and not just treat the acute flare. There is a perception of gout as an acute disease requiring treatment only for acute flares. However, to combat the disease, chronic urate-lowering therapy, reducing the serum urate levels to below the saturation threshold of 6.8 mg/dL, and chronic anti-inflammatory prophylaxis, especially during urate-lowering therapy initiation, are needed. In this manuscript, we discuss some of the contentious issues in gout management. These include the timing of urate-lowering therapy initiation, which urate-lowering therapy to chose, should comorbidities influence our treatment, using genetic determinants, and patient perspectives to drive treatment and differences between gout treatment the American College of Physicians and Rheumatology guidelines for gout management: driving care.

Micrometer aerosol deposition in normal and emphysematous subacinar models.

Emphysema is a chronic respiratory disease characterized by interalveolar septa destruction and enlarged air sacs. How the inhalation dosimetry in the pulmonary acini varies in the time course of emphysema is still unclear. The aim of this study is to numerically evaluate the impact of septal destructions on particle deposition in a pyramid-shape subacinar model that is composed of 496 alveoli. Four emphysematous models were generated by progressively removing the inter-alveolar septa from the normal geometry. Spatial distribution and temporal evolution of particle deposition were quantified in expanding/contracting subacinar models on both total and regional basis using a well-validated discrete-phase Lagrangian model. Airflow fields in the subacinar cavities are sensitive to the septal raptures, with regular, radial streamlines in the proximal alveoli in the normal geometry in contrast to unsymmetrical and recirculating flows in the emphysematous subacini. Intensified collateral ventilation and significantly increased doses in the outer wall and base are observed in disease than heath. The deposition rate of small particles (1-1.5 µm) is more sensitive to the level of septal rapture than large particles (2.5-3 µm). Unexpectedly, more particles per unit area deposit on the outer wall and at the base of the subacinus than on the inner septal walls. The subacinus-averaged doses increase with progressing septal destructions, suggesting an escalating risk factor to the acinar health at the late stages of emphysema.

Leveraging statistical shape modeling in computational respiratory dynamics: Nanomedicine delivery in remodeled airways.

BACKGROUND AND OBJECTIVE: Accurate knowledge of the delivered doses to the diseased site in the respiratory tract is crucial to elicit desired therapeutic outcomes. However, such information is still difficult to obtain due to inaccessibility for measurement or visualization, complex network structure, and challenges in reconstructing lung geometries with disease-invoked airway remodeling. This study presents a novel method to simulate the airway remodeling in a mouth-lung geometry extending to G9. METHODS: Statistical shape modeling was used to extract morphological features from a lung geometry database and four new models (i.e., M1-M4) were generated with parameter-controlled dilated/constricted bronchioles in the left-lower (LL) lung. The variations in airflow and particle deposition due to the airway remodeling were simulated using a well-tested k-ω turbulence model and a Lagrangian tracking approach. RESULTS: Significant variations in flow partitions between the lower and upper lobes of the left lung, as well as between the left and right lungs. The flow partition into the LL lobe varied by 10-fold between the most dilated and constricted models in this study. Significantly lower doses were also predicted on the surface of the constricted LL bronchioles G4-G9, as well as into the peripheral airways beyond G9. However, the total dosimetry in the mouth-lung geometry (up to G9) exhibited low sensitivity to the LL lobar remodeling. Results in this study suggest that the optimal nanomedicine should be 2-10 nm in diameter if targeted at the constricted bronchioles G4-G9 as in topical inhalation therapy but should be larger than 20 nm if targeted at the alveolar region as in systemic therapy. CONCLUSIONS: This study highlights the large dose variability from local airway remodeling and the need to consider these variations in the treatment planning for pneumonia and other obstructive respiratory diseases.

Alveolar size effects on nanoparticle deposition in rhythmically expanding-contracting terminal alveolar models.

Significant differences in alveolar size exist in humans of different ages, gender, health, and among different species. The effects of alveolar sizes, as well as the accompanying breathing frequencies, on regional and local dosimetry of inhaled nanoparticles have not been sufficiently studied. Despite a well-accepted qualitative understanding of the advection-diffusion-sedimentation mechanism in the acinar region, a quantitative picture of the interactions among these factors remains inchoate. The objective of this study is to quantify the effects of alveolar size on the regional and local deposition of inhaled nanoparticles in alveolar models of varying complexities and to understand the dynamic interactions among different deposition mechanisms. Three different models were considered that retained 1, 4, and 45 alveoli, respectively. For each model, the baseline geometry was scaled by », ½, 2, 4, and 8 times by volume. Temporal evolution and spatial distribution of particle deposition were tracked using a discrete-phase Lagrangian model. Lower retentions of inhaled nanoparticles were observed in the larger alveoli under the same respiration frequency, while similar retentions were found among different geometrical scales if breathing frequencies allometrically matched the alveolar size. Dimensional analysis reveals a manifold deposition mechanism with tantamount contributions from advection, diffusion, and gravitational sedimentation, each of which can become dominant depending on the location in the alveoli. Results of this study indicate that empirical correlations obtained from one sub-population cannot be directly applied to others, nor can they be simply scaled as a function of the alveolar size or respiration frequency due to the regime-transiting deposition mechanism that is both localized and dynamic.

Nanoparticle Deposition in Rhythmically Moving Acinar Models with Interalveolar Septal Apertures.

Pulmonary delivery of nanomedicines has been extensively studied in recent years because of their enhanced biocompatibility, sustained-release properties, and surface modification capability. The lung as a target also offers many advantages over other routers, such as large surface area, noninvasive, quick therapeutic onset, and avoiding first-pass metabolism. However, nanoparticles smaller than 0.26 µm typically escape phagocytosis and remain in the alveoli for a long time, leading to particle accumulation and invoking tissue responses. It is imperative to understand the behavior and fates of inhaled nanoparticles in the alveoli to reliably assess therapeutic outcomes of nanomedicines or health risk of environmental toxins. The objective of this study is to numerically investigate nanoparticle deposition in a duct-alveolar model with varying sizes of inter-alveolar septal apertures (pores). A discrete phase Lagrangian model was implemented to track nanoparticle trajectories under the influence of rhythmic wall expansion and contraction. Both temporal and spatial dosimetry in the alveoli were computed. Wall motions are essential for nanoparticles to penetrate the acinar region and deposit in the alveoli. The level of aerosol irreversibility (i.e., mixing of inhaled nanoparticles with residual air in the alveolar airspace) is determined by the particle diffusivity, which in turn, dictates the fraction of particles being exhaled out. When deposition in the upper airways was not considered, high alveolar deposition rates (74-95%) were predicted for all nanoparticles considered (1-1000 nm), which were released into the alveoli at the beginning of the inhalation. The pore size notably affects the deposition pattern of inhaled nanoparticles but exerts a low impact upon the total deposition fractions. This finding indicates that consistent pulmonary doses of nanomedicine are possible in emphysema patients if breathing maneuver with the same tidal volume can be performed.