Local fractal dimension of collagen detects increased spatial complexity in fibrosis.

Increase of collagen content and reorganization characterizes fibrosis but quantifying the latter remains challenging. Spatially complex structures are often analyzed via the fractal dimension; however, established methods for calculating this quantity either provide a single dimension for an entire object or a spatially distributed dimension that only considers binary images. These neglect valuable information related to collagen density in images of fibrotic tissue. We sought to develop a fractal analysis that can be applied to 3-dimensional (3D) images of fibrotic tissue. A fractal dimension map for each image was calculated by determining a single fractal dimension for a small area surrounding each image pixel, using fiber thickness as the third dimension. We found that this local fractal dimension increased with age and with progression of fibrosis regardless of collagen content. Our new method of distributed 3D fractal analysis can thus distinguish between changes in collagen content and organization induced by fibrosis.

Time-Controlled Adaptive Ventilation (TCAV): a personalized strategy for lung protection.

Acute respiratory distress syndrome (ARDS) alters the dynamics of lung inflation during mechanical ventilation. Repetitive alveolar collapse and expansion (RACE) predisposes the lung to ventilator-induced lung injury (VILI). Two broad approaches are currently used to minimize VILI: (1) low tidal volume (LVT) with low-moderate positive end-expiratory pressure (PEEP); and (2) open lung approach (OLA). The LVT approach attempts to protect already open lung tissue from overdistension, while simultaneously resting collapsed tissue by excluding it from the cycle of mechanical ventilation. By contrast, the OLA attempts to reinflate potentially recruitable lung, usually over a period of seconds to minutes using higher PEEP used to prevent progressive loss of end-expiratory lung volume (EELV) and RACE. However, even with these protective strategies, clinical studies have shown that ARDS-related mortality remains unacceptably high with a scarcity of effective interventions over the last two decades. One of the main limitations these varied interventions demonstrate to benefit is the observed clinical and pathologic heterogeneity in ARDS. We have developed an alternative ventilation strategy known as the Time Controlled Adaptive Ventilation (TCAV) method of applying the Airway Pressure Release Ventilation (APRV) mode, which takes advantage of the heterogeneous time- and pressure-dependent collapse and reopening of lung units. The TCAV method is a closed-loop system where the expiratory duration personalizes VT and EELV. Personalization of TCAV is informed and tuned with changes in respiratory system compliance (CRS) measured by the slope of the expiratory flow curve during passive exhalation. Two potentially beneficial features of TCAV are: (i) the expiratory duration is personalized to a given patient's lung physiology, which promotes alveolar stabilization by halting the progressive collapse of alveoli, thereby minimizing the time for the reopened lung to collapse again in the next expiration, and (ii) an extended inspiratory phase at a fixed inflation pressure after alveolar stabilization gradually reopens a small amount of tissue with each breath. Subsequently, densely collapsed regions are slowly ratcheted open over a period of hours, or even days. Thus, TCAV has the potential to minimize VILI, reducing ARDS-related morbidity and mortality.

Positive- and Negative-Pressure Ventilation Characterized by Local and Global Pulmonary Mechanics.

Rationale: There is continued debate regarding the equivalency of positive-pressure ventilation (PPV) and negative-pressure ventilation (NPV). Resolving this question is important because of the different practical ramifications of the two paradigms. Objectives: We sought to investigate the parallel between PPV and NPV and determine whether or not these two paradigms cause identical ventilation profiles by analyzing the local strain mechanics when the global tidal volume (Vt) and inflation pressure was matched. Methods: A custom-designed electromechanical apparatus was used to impose equal global loads and displacements on the same ex vivo healthy porcine lung using PPV and NPV. High-speed high-resolution cameras recorded local lung surface deformations and strains in real time, and differences between PPV and NPV global energetics, viscoelasticity, as well as local tissue distortion were assessed. Measurements and Main Results: During initial inflation, NPV exhibited significantly more bulk pressure-volume compliance than PPV, suggestive of earlier lung recruitment. NPV settings also showed reduced relaxation, hysteresis, and energy loss compared with PPV. Local strain trends were also decreased in NPV, with reduced tissue distortion trends compared with PPV, as revealed through analysis of tissue anisotropy. Conclusions: Apparently, contradictory previous studies are not mutually exclusive. Equivalent changes in transpulmonary pressures in PPV and NPV lead to the same changes in lung volume and pressures, yet local tissue strains differ between PPV and NPV. Although limited to healthy specimens and ex vivo experiments in the absence of a chest cavity, these results may explain previous reports of better oxygenation and less lung injury in NPV.

An agent-based model of tissue maintenance and self-repair.

We hypothesized that a system that possesses the capacity for ongoing maintenance of its tissues will necessarily also have the capacity to self-heal following a perturbation. We used an agent-based model of tissue maintenance to investigate this idea, and in particular to determine the extent to which the current state of the tissue must influence cell behavior in order for tissue maintenance and self-healing to be stable. We show that a mean level of tissue density is robustly maintained when catabolic agents digest tissue at a rate proportional to local tissue density, but that the spatial heterogeneity of the tissue at homeostasis increases with the rate at which tissue is digested. The rate of self-healing is also increased by increasing either the amount of tissue removed or deposited at each time step by catabolic or anabolic agents, respectively, and by increasing the density of both agent types on the tissue. We also found that tissue maintenance and self-healing are stable with an alternate rule in which cells move preferentially to tissue regions of low density. The most basic form of self-healing can thus be achieved with cells that follow very simple rules of behavior, provided these rules are based in some way on the current state of the local tissue. Straightforward mechanisms can accelerate the rate of self-healing, as might be beneficial to the organism.

The effect of inhaled extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide on distal and central airway indices, assessed using Functional Respiratory Imaging in COPD (DARWiIN).

BACKGROUND: This study, in patients with symptomatic chronic obstructive pulmonary disease (COPD), explored switching therapy from non-extrafine high-dose inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA; fluticasone propionate/salmeterol [FP/SLM]) to extrafine medium-dose beclometasone dipropionate/formoterol fumarate dihydrate/glycopyrronium (BDP/FF/G), both via dry-powder inhaler. Functional Respiratory Imaging, a quantitative computed tomography method with 3D reconstructions of pulmonary anatomy, was used to assess airway geometry and lung function. METHODS: Patients receiving a stable ICS/LABA regimen for ≥ 8 weeks were switched to FP/SLM 500/50 µg, one inhalation twice-daily (high-dose ICS) for 6 weeks. After baseline assessments (Visit 2 [V2]), therapy was switched to BDP/FF/G 100/6/10 µg, two inhalations twice-daily (medium-dose ICS) for 6 weeks, followed by V3. The primary endpoints were percentage changes in specific image-based airway volume (siVaw) and resistance (siRaw) from baseline to predose at V3 (i.e., chronic effects), assessed at total lung capacity (TLC) in central and distal lung regions. Secondary endpoints included siVaw and siRaw changes from pre-dose to post-dose at V2, and from pre-dose to post-dose at V3 at TLC (i.e., acute effects), and chronic and acute changes in siVaw and siRaw at functional residual capacity (FRC). Pre-dose forced expiratory volume in 1 s (FEV1) and COPD Assessment Test (CAT) were also assessed. RESULTS: There were no significant changes in pre-dose siVaw or siRaw at TLC from baseline to V3, although at FRC there was a significant decrease in mean siRaw in the distal airways (- 63.6%; p = 0.0261). In addition, in the distal airways there were significant acute effects at TLC on mean siVaw and siRaw (siVaw: 39.8% and 62.6%; siRaw: - 51.1% and - 57.2%, V2 and V3, respectively; all p < 0.001) and at FRC at V2 (siVaw: 77.9%; siRaw: - 67.0%; both p < 0.001). At V3, the mean change in pre-dose FEV1 was 62.2 mL (p = 0.0690), and in CAT total score was - 3.30 (p < 0.0001). CONCLUSIONS: In patients with symptomatic COPD receiving high-dose ICS/LABA, adding a long-acting muscarinic antagonist while decreasing the ICS dose by switching to medium-dose extrafine BDP/FF/G was associated with improved airway indices, especially in the distal airways, together with improvements in respiratory health status. Trial registration ClinicalTrials.gov (NCT04876677), first posted 6th May 2021.

Model analysis of multiple breath nitrogen washout data: robustness to variations in breathing pattern.

We recently developed a model-based method for analyzing multiple breath nitrogen washout data that does not require identification of Phase-III. In the present study, we assessed the effect of irregular breathing patterns on the intra-subject variabilities of the model parameters. Nitrogen fraction at the mouth was measured in 18 healthy and 20 asthmatic subjects during triplicate performances of multiple breath nitrogen washout, during controlled (target tidal volume 1 L at 8-12 breaths per minute) and free (unrestricted) breathing. The parameters Scond, Sacin and functional residual capacity (FRC) were obtained by conventional analysis of the slope of Phase-III. Fitting the model to the washout data provided functional residual capacity (FRCM), dead space volume (VD), the coefficient of variation of regional specific ventilation ([Formula: see text]), and the model equivalent of Sacin (Sacin-M). Intra-participant coefficients of variation for the model parameters for both health and asthma were FRCM < 5.2%, VD < 5.4%, [Formula: see text] < 9.0%, and Sacin-M < 45.6% for controlled breathing, and FRCM < 4.6%, VD < 5.3%, [Formula: see text] < 13.2%, and Sacin-M < 103.2% for free breathing. The coefficients of variation limits for conventional parameters were FRC < 6.1%, with Scond < 73.6% and Sacin < 49.2% for controlled breathing and Scond < 35.0% and Sacin < 74.4% for free breathing. The model-fitting approach to multiple breath nitrogen washout analysis provides a measure of regional ventilation heterogeneity in [Formula: see text] that is less affected by irregularities in the breathing pattern than its corresponding Phase-III slope analysis parameter Scond.

Update on the Features and Measurements of Experimental Acute Lung Injury in Animals: An Official American Thoracic Society Workshop Report.

Advancements in methods, technology, and our understanding of the pathobiology of lung injury have created the need to update the definition of experimental acute lung injury (ALI). We queried 50 participants with expertise in ALI and acute respiratory distress syndrome using a Delphi method composed of a series of electronic surveys and a virtual workshop. We propose that ALI presents as a "multidimensional entity" characterized by four "domains" that reflect the key pathophysiologic features and underlying biology of human acute respiratory distress syndrome. These domains are 1) histological evidence of tissue injury, 2) alteration of the alveolar-capillary barrier, 3) presence of an inflammatory response, and 4) physiologic dysfunction. For each domain, we present "relevant measurements," defined as those proposed by at least 30% of respondents. We propose that experimental ALI encompasses a continuum of models ranging from those focusing on gaining specific mechanistic insights to those primarily concerned with preclinical testing of novel therapeutics or interventions. We suggest that mechanistic studies may justifiably focus on a single domain of lung injury, but models must document alterations of at least three of the four domains to qualify as "experimental ALI." Finally, we propose that a time criterion defining "acute" in ALI remains relevant, but the actual time may vary based on the specific model and the aspect of injury being modeled. The continuum concept of ALI increases the flexibility and applicability of the definition to multiple models while increasing the likelihood of translating preclinical findings to critically ill patients.

Discriminating TB lung nodules from early lung cancers using deep learning.

BACKGROUND: In developing countries where both high rates of smoking and endemic tuberculosis (TB) are often present, identification of early lung cancer can be significantly confounded by the presence of nodules such as those due to latent TB (LTB). It is very challenging to distinguish lung cancer and LTB without invasive procedures, which have their own risks of morbidity and even mortality. METHODS: Our method uses a customized VGG16-based 15-layer 2-dimensional deep convolutional neural network (DNN) architecture with transfer learning. The DNN was trained and tested on sets of CT images set extracted from the National Lung Screening Trial and the National Institute of Allergy and Infectious Disease TB Portals. Performance of the DNN was evaluated under locked and step-wise unlocked pretrained weight conditions. RESULTS: The DNN with unlocked pretrained weights achieved an accuracy of 90.4% with an F score of 90.1%. CONCLUSIONS: Our findings support the potential for a DNN to serve as a noninvasive screening tool capable of reliably detecting and distinguishing between lung cancer and LTB.

What is new in respiratory monitoring?

This paper provides a review of a selection of papers published in the Journal of Clinical Monitoring and Computing in 2020 and 2021 highlighting what is new within the field of respiratory monitoring. Selected papers cover work in pulse oximetry monitoring, acoustic monitoring, respiratory system mechanics, monitoring during surgery, electrical impedance tomography, respiratory rate monitoring, lung ultrasound and detection of patient-ventilator asynchrony.

Wavelet decomposition facilitates training on small datasets for medical image classification by deep learning.

The adoption of low-dose computed tomography (LDCT) as the standard of care for lung cancer screening results in decreased mortality rates in high-risk population while increasing false-positive rate. Convolutional neural networks provide an ideal opportunity to improve malignant nodule detection; however, due to the lack of large adjudicated medical datasets these networks suffer from poor generalizability and overfitting. Using computed tomography images of the thorax from the National Lung Screening Trial (NLST), we compared discrete wavelet transforms (DWTs) against convolutional layers found in a CNN in order to evaluate their ability to classify suspicious lung nodules as either malignant or benign. We explored the use of the DWT as an alternative to the convolutional operations within CNNs in order to decrease the number of parameters to be estimated during training and reduce the risk of overfitting. We found that multi-level DWT performed better than convolutional layers when multiple kernel resolutions were utilized, yielding areas under the receiver-operating curve (AUC) of 94% and 92%, respectively. Furthermore, we found that multi-level DWT reduced the number of network parameters requiring evaluation when compared to a CNN and had a substantially faster convergence rate. We conclude that utilizing multi-level DWT composition in place of early convolutional layers within a DNN may improve for image classification in data-limited domains.

Central airway collapse is related to obesity independent of asthma phenotype.

BACKGROUND AND OBJECTIVE: Late-onset non-allergic asthma in obesity is characterized by an abnormally compliant, collapsible lung periphery; it is not known whether this abnormality exists in proximal airways. We sought to compare collapsibility of central airways between lean and obese individuals with and without asthma. METHODS: A cross-sectional study comparing luminal area and shape (circularity) of the trachea, left mainstem bronchus, right bronchus intermedius and right inferior lobar bronchus at RV and TLC by CT was conducted. RESULTS: In 11 lean controls (BMI: 22.4 (21.5, 23.8) kg/m2 ), 10 lean individuals with asthma (23.6 (22.0, 24.8) kg/m2 ), 10 obese controls (45.5 (40.3, 48.5) kg/m2 ) and 21 obese individuals with asthma (39.2 (35.8, 42.9) kg/m2 ), lumen area and circularity increased significantly with an increase in lung volume from RV to TLC for all four airways (P < 0.05 for all). Changes in area and circularity with lung volume were similar in obese individuals with and without asthma, and both obese groups had severe airway collapse at RV. In multivariate analysis, change in lumen area was related to BMI and change in circularity to waist circumference, but neither was related to asthma diagnosis. CONCLUSION: Excessive collapse of the central airways is related to obesity, and occurs in both obese controls and obese asthma. Increased airway collapse could contribute to ventilation abnormalities in obese individuals particularly at lower lung volumes, and complicate asthma in obese individuals.

The POOR Get POORer: A Hypothesis for the Pathogenesis of Ventilator-induced Lung Injury.

Protective ventilation strategies for the injured lung currently revolve around the use of low Vt, ostensibly to avoid volutrauma, together with positive end-expiratory pressure to increase the fraction of open lung and reduce atelectrauma. Protective ventilation is currently applied in a one-size-fits-all manner, and although this practical approach has reduced acute respiratory distress syndrome deaths, mortality is still high and improvements are at a standstill. Furthermore, how to minimize ventilator-induced lung injury (VILI) for any given lung remains controversial and poorly understood. Here we present a hypothesis of VILI pathogenesis that potentially serves as a basis upon which minimally injurious ventilation strategies might be developed. This hypothesis is based on evidence demonstrating that VILI begins in isolated lung regions manifesting a Permeability-Originated Obstruction Response (POOR) in which alveolar leak leads to surfactant dysfunction and increases local tissue stresses. VILI progresses topographically outward from these regions in a POOR-get-POORer fashion unless steps are taken to interrupt it. We propose that interrupting the POOR-get-POORer progression of lung injury relies on two principles: 1) open the lung to minimize the presence of heterogeneity-induced stress concentrators that are focused around the regions of atelectasis, and 2) ventilate in a patient-dependent manner that minimizes the number of lung units that close during each expiration so that they are not forced to rerecruit during the subsequent inspiration. These principles appear to be borne out in both patient and animal studies in which expiration is terminated before derecruitment of lung units has enough time to occur.

Body Habitus and Dynamic Surgical Conditions Independently Impair Pulmonary Mechanics during Robotic-assisted Laparoscopic Surgery.

BACKGROUND: Body habitus, pneumoperitoneum, and Trendelenburg positioning may each independently impair lung mechanics during robotic laparoscopic surgery. This study hypothesized that increasing body mass index is associated with more mechanical strain and alveolar collapse, and these impairments are exacerbated by pneumoperitoneum and Trendelenburg positioning. METHODS: This cross-sectional study measured respiratory flow, airway pressures, and esophageal pressures in 91 subjects with body mass index ranging from 18.3 to 60.6 kg/m2. Pulmonary mechanics were quantified at four stages: (1) supine and level after intubation, (2) with pneumoperitoneum, (3) in Trendelenburg docked with the surgical robot, and (4) level without pneumoperitoneum. Subjects were stratified into five body mass index categories (less than 25, 25 to 29.9, 30 to 34.9, 35 to 39.9, and 40 or higher), and respiratory mechanics were compared over surgical stages using generalized estimating equations. The optimal positive end-expiratory pressure settings needed to achieve positive end-expiratory transpulmonary pressures were calculated. RESULTS: At baseline, transpulmonary driving pressures increased in each body mass index category (1.9 ± 0.5 cm H2O; mean difference ± SD; P < 0.006), and subjects with a body mass index of 40 or higher had decreased mean end-expiratory transpulmonary pressures compared with those with body mass index of less than 25 (-7.5 ± 6.3 vs. -1.3 ± 3.4 cm H2O; P < 0.001). Pneumoperitoneum and Trendelenburg each further elevated transpulmonary driving pressures (2.8 ± 0.7 and 4.7 ± 1.0 cm H2O, respectively; P < 0.001) and depressed end-expiratory transpulmonary pressures (-3.4 ± 1.3 and -4.5 ± 1.5 cm H2O, respectively; P < 0.001) compared with baseline. Optimal positive end-expiratory pressure was greater than set positive end-expiratory pressure in 79% of subjects at baseline, 88% with pneumoperitoneum, 95% in Trendelenburg, and ranged from 0 to 36.6 cm H2O depending on body mass index and surgical stage. CONCLUSIONS: Increasing body mass index induces significant alterations in lung mechanics during robotic laparoscopic surgery, but there is a wide range in the degree of impairment. Positive end-expiratory pressure settings may need individualization based on body mass index and surgical conditions.

Modeling the impact of school reopening on SARS-CoV-2 transmission using contact structure data from Shanghai.

BACKGROUND: Mathematical modeling studies have suggested that pre-emptive school closures alone have little overall impact on SARS-CoV-2 transmission, but reopening schools in the background of community contact reduction presents a unique scenario that has not been fully assessed. METHODS: We adapted a previously published model using contact information from Shanghai to model school reopening under various conditions. We investigated different strategies by combining the contact patterns observed between different age groups during both baseline and "lockdown" periods. We also tested the robustness of our strategy to the assumption of lower susceptibility to infection in children under age 15 years. RESULTS: We find that reopening schools for all children would maintain a post-intervention R0 < 1 up to a baseline R0 of approximately 3.3 provided that daily contacts among children 10-19 years are reduced to 33% of baseline. This finding was robust to various estimates of susceptibility to infection in children relative to adults (up to 50%) and to estimates of various levels of concomitant reopening in the rest of the community (up to 40%). However, full school reopening without any degree of contact reduction in the school setting returned R0 virtually back to baseline, highlighting the importance of mitigation measures. CONCLUSIONS: These results, based on contact structure data from Shanghai, suggest that schools can reopen with proper precautions during conditions of extreme contact reduction and during conditions of reasonable levels of reopening in the rest of the community.

Classification and Detection of Breathing Patterns with Wearable Sensors and Deep Learning.

Rapid assessment of breathing patterns is important for several emergency medical situations. In this research, we developed a non-invasive breathing analysis system that automatically detects different types of breathing patterns of clinical significance. Accelerometer and gyroscopic data were collected from light-weight wireless sensors placed on the chest and abdomen of 100 normal volunteers who simulated various breathing events (central sleep apnea, coughing, obstructive sleep apnea, sighing, and yawning). We then constructed synthetic datasets by injecting annotated examples of the various patterns into segments of normal breathing. A one-dimensional convolutional neural network was implemented to detect the location of each event in each synthetic dataset and to classify it as belonging to one of the above event types. We achieved a mean F1 score of 92% for normal breathing, 87% for central sleep apnea, 72% for coughing, 51% for obstructive sleep apnea, 57% for sighing, and 63% for yawning. These results demonstrate that using deep learning to analyze chest and abdomen movement data from wearable sensors provides an unobtrusive means of monitoring the breathing pattern. This could have application in a number of critical medical situations such as detecting apneas during sleep at home and monitoring breathing events in mechanically ventilated patients in the intensive care unit.

Sources of breathing pattern variability in the respiratory feedback control loop.

The variability of the breath-to-breath breathing pattern, and its alterations in disease, may hold information of physiologic and/or diagnostic value. We hypothesized that this variability arises from the way that noise is processed within the respiratory feedback control loop, and that pathologic alterations to specific components within the system give rise to characteristic alterations in breathing pattern variability. We explored this hypothesis using a computational model of the respiratory control system that integrates mechanical factors, gas exchange processes, and chemoreceptor signals to simulate breathing patterns subject to the influences of random variability in each of the system components. We found that the greatest changes in the coefficient of variation (CV) of both breathing amplitude and timing were caused by increases in lung resistance and impairments in gas exchange, both common features of pulmonary disease. This suggests that breathing pattern variability may reflect discernible deterministic processes involved in the control of breathing.

BMI but not central obesity predisposes to airway closure during bronchoconstriction.

BACKGROUND AND OBJECTIVE: Obesity produces restrictive effects on lung function. We previously reported that obese patients with asthma exhibit a propensity towards small airway closure during methacholine challenge which improved with weight loss. We hypothesized that increased abdominal adiposity, a key contributor to the restrictive effects of obesity on the lung, mediates this response. This study investigates the effect of body mass index (BMI) versus waist circumference (WC) on spirometric lung function, sensitivity to airway narrowing and closure, and airway closure during bronchoconstriction in patients with asthma. METHODS: Participants underwent spirometry and methacholine challenge. Sensitivity to airway closure and narrowing was assessed from the dose-response slopes of the forced vital capacity (FVC) and the ratio of forced expiratory volume in 1 s (FEV1 ) to FVC, respectively. Airway closure during bronchoconstriction (closing index) was computed as the percent reduction in FVC divided by the percent reduction in FEV1 at maximal bronchoconstriction. RESULTS: A total of 116 asthmatic patients (56 obese) underwent methacholine challenge. Spirometric lung function was inversely related to WC (P < 0.05), rather than BMI. Closing index increased significantly during bronchoconstriction in obese patients and was related to increasing BMI (P = 0.01), but not to WC. Sensitivity to airway closure and narrowing was not associated with BMI or WC. CONCLUSION: Although WC is associated with restrictive effects on baseline lung function, increased BMI, rather than WC, predisposes to airway closure during bronchoconstriction. These findings suggest that obesity predisposes to airway closure during bronchoconstriction through mechanisms other than simple mass loading.