Examining patient demographics and major adverse cardiac events following noncardiac surgery: Applying a health equity lens.

BACKGROUND: Major adverse cardiac events (MACE) are a major contributor to postoperative complications. This study employed a health equity lens to examine rates of postoperative MACE by race and ethnicity. METHODS: This single-center, retrospective observational cohort study followed patients with and without pre-existing coronary artery stents from 2008 to 2018 who underwent non-cardiac surgery. MACE was the primary outcome (death, acute MI, repeated coronary revascularization, in-stent thrombosis) and self-reported race and ethnicity was the primary predictor. A propensity score model of a 1:1 cohort of non-Hispanic White (NHW) patients and all other racial and ethnic minority populations (Hispanic and Black) was used to compare the rate of perioperative MACE in this cohort. RESULTS: During the study period, 79,686 cases were included in the analytic sample; 950 patients (1.2 %) had pre-existing coronary artery stents. <1 % of patients experienced MACE within 30 days following non-cardiac surgery (0.8 %). After confounder adjustment and propensity score matching, there were no statistically significant differences in MACE among racial and ethnic minority patients compared to NHW patients (OR = 0.77; 95 % CI: 0.48, 1.25). In our sensitivity analyses, stratifying by sex, there were no differences in MACE by race and ethnicity. CONCLUSIONS: The study found no statistically significant differences in MACE by race and ethnicity among patients who underwent non-cardiac surgery. Access to a high-volume, high-quality hospital such as the one studied may reduce the presence of healthcare disparities and may explain why our findings are not consistent with previous studies.

The fix is not yet in: recommendation for fixation of lungs within physiologic/pathophysiologic volume range in preclinical pulmonary structure-function studies.

Quantitative characterization of lung structures by morphometric or stereologic analysis of histologic sections is a powerful means of elucidating pulmonary structure-function relations. The overwhelming majority of studies, however, fix lungs for histology at pressures outside the physiologic/pathophysiologic respiratory volume range. Thus valuable information is being lost. In this perspective article, we argue that investigators performing pulmonary histologic studies should consider whether the aims of their studies would benefit from fixation at functional transpulmonary pressures, particular those of end-inspiration and end-expiration. We survey the pressures at which lungs are typically fixed in preclinical structure-function studies; provide examples of conditions that would benefit from histologic evaluation at functional lung volumes; summarize available fixation methods; discuss alternative imaging modalities; and discuss challenges to implementing the suggested approach and means of addressing those challenges. We aim to persuade investigators that modifying or complementing the traditional histologic approach by fixing lungs at minimal and maximal functional volumes could enable new understanding of pulmonary structure-function relations.

A scale-free model of acute and ventilator-induced lung injury: a network theory approach inspired by seismology.

Introduction: Acute respiratory distress syndrome (ARDS) presents a significant clinical challenge, with ventilator-induced lung injury (VILI) being a critical complication arising from life-saving mechanical ventilation. Understanding the spatial and temporal dynamics of VILI can inform therapeutic strategies to mitigate lung damage and improve outcomes. Methods: Histological sections from initially healthy mice and pulmonary lavage-injured mice subjected to a second hit of VILI were segmented with Ilastik to define regions of lung injury. A scale-free network approach was applied to assess the correlation between injury regions, with regions of injury represented as 'nodes' in the network and 'edges' quantifying the degree of correlation between nodes. A simulated time series analysis was conducted to emulate the temporal sequence of injury events. Results: Automated segmentation identified different lung regions in good agreement with manual scoring, achieving a sensitivity of 78% and a specificity of 85% across 'injury' pixels. Overall accuracy across 'injury', 'air', and 'other' pixels was 81%. The size of injured regions followed a power-law distribution, suggesting a 'rich-get-richer' phenomenon in the distribution of lung injury. Network analysis revealed a scale-free distribution of injury correlations, highlighting hubs of injury that could serve as focal points for therapeutic intervention. Simulated time series analysis further supported the concept of secondary injury events following an initial insult, with patterns resembling those observed in seismological studies of aftershocks. Conclusion: The size distribution of injured regions underscores the spatially heterogeneous nature of acute and ventilator-induced lung injury. The application of network theory demonstrates the emergence of injury 'hubs' that are consistent with a 'rich-get-richer' dynamic. Simulated time series analysis demonstrates that the progression of injury events in the lung could follow spatiotemporal patterns similar to the progression of aftershocks in seismology, providing new insights into the mechanisms of injury distribution and propagation. Both phenomena suggest a potential for interventions targeting these injury 'hubs' to reduce the impact of VILI in ARDS management.

Low-volume ventilation of preinjured lungs degrades lung function via stress concentration and progressive alveolar collapse.

Mechanical ventilation can cause ventilation-induced lung injury (VILI). The concept of stress concentrations suggests that surfactant dysfunction-induced microatelectases might impose injurious stresses on adjacent, open alveoli and function as germinal centers for injury propagation. The aim of the present study was to quantify the histopathological pattern of VILI progression and to test the hypothesis that injury progresses at the interface between microatelectases and ventilated lung parenchyma during low-positive end-expiratory pressure (PEEP) ventilation. Bleomycin was used to induce lung injury with microatelectases in rats. Lungs were then mechanically ventilated for up to 6 h at PEEP = 1 cmH2O and compared with bleomycin-treated group ventilated protectively with PEEP = 5 cmH2O to minimize microatelectases. Lung mechanics were measured during ventilation. Afterward, lungs were fixed at end-inspiration or end-expiration for design-based stereology. Before VILI, bleomycin challenge reduced the number of open alveoli [N(alvair,par)] by 29%. No differences between end-inspiration and end-expiration were observed. Collapsed alveoli clustered in areas with a radius of up to 56 µm. After PEEP = 5 cmH2O ventilation for 6 h, N(alvair,par) remained stable while PEEP = 1 cmH2O ventilation led to an additional loss of aerated alveoli by 26%, mainly due to collapse, with a small fraction partly edema filled. Alveolar loss strongly correlated to worsening of tissue elastance, quasistatic compliance, and inspiratory capacity. The radius of areas of collapsed alveoli increased to 94 µm, suggesting growth of the microatelectases. These data provide evidence that alveoli become unstable in neighborhood of microatelectases, which most likely occurs due to stress concentration-induced local vascular leak and surfactant dysfunction.NEW & NOTEWORTHY Low-volume mechanical ventilation in the presence of high surface tension-induced microatelectases leads to the degradation of lung mechanical function via the progressive loss of alveoli. Microatelectases grow at the interfaces of collapsed and open alveoli. Here, stress concentrations might cause injury and alveolar instability. Accumulation of small amounts of alveolar edema can be found in a fraction of partly collapsed alveoli but, in this model, alveolar flooding is not a major driver for degradation of lung mechanics.

The role of methadone in cardiac surgery for management of postoperative pain.

Background: This retrospective study evaluated the efficacy and safety of intraoperative methadone compared with short-acting opioids. Methods: Patients undergoing cardiac surgery with cardiopulmonary bypass (n=11 967) from 2018 to 2023 from a single health system were categorised into groups based on intraoperative opioid administration: no methadone (Group O), methadone plus other opioids (Group M+O), and methadone only (Group M). Results: Patients in Groups M and M+O had lower mean pain scores until postoperative day (POD) 7 compared with Group O after adjusting for covariates (P<0.01). Both Groups M and M+O had lower total opioid administered compared with Group O for all days POD0-POD6 (all P<0.001). The median number of hours until initial postoperative opioid after surgery was 2.55 (inter-quartile range [IQR]=1.07-5.12), 6.82 (IQR=3.52-12.98), and 7.0 (IQR=3.82-12.95) for Group O, Group M+O, and Group M, respectively. The incidence of postoperative complications did not differ between groups. Conclusions: Intraoperative administration of methadone was associated with better pain control without significant side-effects after cardiac surgery.

Exploring alveolar recruitability using positive end-expiratory pressure in mice overexpressing TGF-ß1: a structure-function analysis.

Pre-injured lungs are prone to injury progression in response to mechanical ventilation. Heterogeneous ventilation due to (micro)atelectases imparts injurious strains on open alveoli (known as volutrauma). Hence, recruitment of (micro)atelectases by positive end-expiratory pressure (PEEP) is necessary to interrupt this vicious circle of injury but needs to be balanced against acinar overdistension. In this study, the lung-protective potential of alveolar recruitment was investigated and balanced against overdistension in pre-injured lungs. Mice, treated with empty vector (AdCl) or adenoviral active TGF-ß1 (AdTGF-ß1) were subjected to lung mechanical measurements during descending PEEP ventilation from 12 to 0 cmH2O. At each PEEP level, recruitability tests consisting of two recruitment maneuvers followed by repetitive forced oscillation perturbations to determine tissue elastance (H) and damping (G) were performed. Finally, lungs were fixed by vascular perfusion at end-expiratory airway opening pressures (Pao) of 20, 10, 5 and 2 cmH2O after a recruitment maneuver, and processed for design-based stereology to quantify derecruitment and distension. H and G were significantly elevated in AdTGF-ß1 compared to AdCl across PEEP levels. H was minimized at PEEP = 5-8 cmH2O and increased at lower and higher PEEP in both groups. These findings correlated with increasing septal wall folding (= derecruitment) and reduced density of alveolar number and surface area (= distension), respectively. In AdTGF-ß1 exposed mice, 27% of alveoli remained derecruited at Pao = 20 cmH2O. A further decrease in Pao down to 2 cmH2O showed derecruitment of an additional 1.1 million alveoli (48%), which was linked with an increase in alveolar size heterogeneity at Pao = 2-5 cmH2O. In AdCl, decreased Pao resulted in septal folding with virtually no alveolar collapse. In essence, in healthy mice alveoli do not derecruit at low PEEP ventilation. The potential of alveolar recruitability in AdTGF-ß1 exposed mice is high. H is optimized at PEEP 5-8 cmH2O. Lower PEEP folds and larger PEEP stretches septa which results in higher H and is more pronounced in AdTGF-ß1 than in AdCl. The increased alveolar size heterogeneity at Pao = 5 cmH2O argues for the use of PEEP = 8 cmH2O for lung protective mechanical ventilation in this animal model.

Quantifiable identification of flow-limited ventilator dyssynchrony with the deformed lung ventilator model.

BACKGROUND: Ventilator dyssynchrony (VD) can worsen lung injury and is challenging to detect and quantify due to the complex variability in the dyssynchronous breaths. While machine learning (ML) approaches are useful for automating VD detection from the ventilator waveform data, scalable severity quantification and its association with pathogenesis and ventilator mechanics remain challenging. OBJECTIVE: We develop a systematic framework to quantify pathophysiological features observed in ventilator waveform signals such that they can be used to create feature-based severity stratification of VD breaths. METHODS: A mathematical model was developed to represent the pressure and volume waveforms of individual breaths in a feature-based parametric form. Model estimates of respiratory effort strength were used to assess the severity of flow-limited (FL)-VD breaths compared to normal breaths. A total of 93,007 breath waveforms from 13 patients were analyzed. RESULTS: A novel model-defined continuous severity marker was developed and used to estimate breath phenotypes of FL-VD breaths. The phenotypes had a predictive accuracy of over 97% with respect to the previously developed ML-VD identification algorithm. To understand the incidence of FL-VD breaths and their association with the patient state, these phenotypes were further successfully correlated with ventilator-measured parameters and electronic health records. CONCLUSION: This work provides a computational pipeline to identify and quantify the severity of FL-VD breaths and paves the way for a large-scale study of VD causes and effects. This approach has direct application to clinical practice and in meaningful knowledge extraction from the ventilator waveform data.

Flow-Limited and Reverse-Triggered Ventilator Dyssynchrony Are Associated With Increased Tidal and Dynamic Transpulmonary Pressure.

OBJECTIVES: Ventilator dyssynchrony may be associated with increased delivered tidal volumes (V t s) and dynamic transpulmonary pressure (ΔP L,dyn ), surrogate markers of lung stress and strain, despite low V t ventilation. However, it is unknown which types of ventilator dyssynchrony are most likely to increase these metrics or if specific ventilation or sedation strategies can mitigate this potential. DESIGN: A prospective cohort analysis to delineate the association between ten types of breaths and delivered V t , ΔP L,dyn , and transpulmonary mechanical energy. SETTING: Patients admitted to the medical ICU. PATIENTS: Over 580,000 breaths from 35 patients with acute respiratory distress syndrome (ARDS) or ARDS risk factors. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients received continuous esophageal manometry. Ventilator dyssynchrony was identified using a machine learning algorithm. Mixed-effect models predicted V t , ΔP L,dyn , and transpulmonary mechanical energy for each type of ventilator dyssynchrony while controlling for repeated measures. Finally, we described how V t , positive end-expiratory pressure (PEEP), and sedation (Richmond Agitation-Sedation Scale) strategies modify ventilator dyssynchrony's association with these surrogate markers of lung stress and strain. Double-triggered breaths were associated with the most significant increase in V t , ΔP L,dyn , and transpulmonary mechanical energy. However, flow-limited, early reverse-triggered, and early ventilator-terminated breaths were also associated with significant increases in V t , ΔP L,dyn , and energy. The potential of a ventilator dyssynchrony type to increase V t , ΔP L,dyn , or energy clustered similarly. Increasing set V t may be associated with a disproportionate increase in high-volume and high-energy ventilation from double-triggered breaths, but PEEP and sedation do not clinically modify the interaction between ventilator dyssynchrony and surrogate markers of lung stress and strain. CONCLUSIONS: Double-triggered, flow-limited, early reverse-triggered, and early ventilator-terminated breaths are associated with increases in V t , ΔP L,dyn , and energy. As flow-limited breaths are more than twice as common as double-triggered breaths, further work is needed to determine the interaction of ventilator dyssynchrony frequency to cause clinically meaningful changes in patient outcomes.

Identifying low-dimensional trajectories of mechanically-ventilated patient systems: Empirical phenotypes of joint patient+care processes to enhance temporal analysis in ARDS research.

Refined management of mechanically ventilation is an obvious target for improving patient outcomes, but is impeded by the nature of data for study and hypothesis generation. The connections between clinical outcomes and temporal development of iatrogenic injuries current lung-protective ventilator settings remain poorly understood. Analysis of lung-ventilator system (LVS) evolution at relevant timescales is frustrated by data volume and multiple sources of heterogeneity. This work motivates, presents, and validates a computational pipeline for resolving LVS systems into the joint evolution of data-conditioned model parameters and ventilator information. Applied to individuals, the workflow yields a concise low-dimensional representation of LVS behavior expressed in phenotypic breath waveforms suitable for analysis. The effectiveness of this approach is demonstrated through application to multi-day observational series of 35 patients. Individual patient analyses reveal multiple types of patient-oriented dynamics and breath behavior to expose the complexity of LVS evolution; less than 10% of phenotype changes related to ventilator settings changes. Dynamics are shown to including both stable and unstable phenotype transitions as well as both discrete and continuous changes unrelated to ventilator settings. At a cohort scale, 721 phenotypes constructed from individual data are condensed into a set of 16 groups that empirically organize around certain settings (positive end-expository pressure and ventilator mode) and structurally similar pressure-volume loop characterizations. Individual and cohort scale phenotypes, which may be refined by hypothesis-specific constructions, provide a common framework for ongoing temporal analysis and investigation of LVS dynamics.

Antenatal Endotoxin Induces Dysanapsis in Experimental Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is characterized by impaired lung development with sustained functional abnormalities due to alterations of airways and the distal lung. Although clinical studies have shown striking associations between antenatal stress and BPD, little is known about the underlying pathogenetic mechanisms. Whether dysanapsis, the concept of discordant growth of the airways and parenchyma, contributes to late respiratory disease as a result of antenatal stress is unknown. We hypothesized that antenatal endotoxin (ETX) impairs juvenile lung function as a result of altered central airway and distal lung structure, suggesting the presence of dysanapsis in this preclinical BPD model. Fetal rats were exposed to intraamniotic ETX (10 µg) or saline solution (control) 2 days before term. We performed extensive structural and functional evaluation of the proximal airways and distal lung in 2-week-old rats. Distal lung structure was quantified by stereology. Conducting airway diameters were measured using micro-computed tomography. Lung function was assessed during invasive ventilation to quantify baseline mechanics, response to methacholine challenge, and spirometry. ETX-exposed pups exhibited distal lung simplification, decreased alveolar surface area, and decreased parenchyma-airway attachments. ETX-exposed pups exhibited decreased tracheal and second- and third-generation airway diameters. ETX increased respiratory system resistance and decreased lung compliance at baseline. Only Newtonian resistance, specific to large airways, exhibited increased methacholine reactivity in ETX-exposed pups compared with controls. ETX-exposed pups had a decreased ratio of FEV in 0.1 second to FVC and a normal FEV in 0.1 second, paralleling the clinical definition of dysanapsis. Antenatal ETX causes abnormalities of the central airways and distal lung growth, suggesting that dysanapsis contributes to abnormal lung function in juvenile rats.

Days Alive and Out of the Hospital After Heart Transplantation: A Retrospective Cohort Study.

OBJECTIVE: Evaluate days alive and out of the hospital (DAOH) as an outcome measure after orthotopic heart transplantation in patients with mechanical circulatory support (MCS) as a bridge to transplant compared to those patients without prior MCS. DESIGN: A retrospective observational study of adult patients who underwent cardiac transplantation between January 1, 2015, and January 1, 2020. The primary outcome was DAOH at 365 days (DAOH365) after an orthotopic heart transplant. A Poisson regression model was fitted to detect the association between independent variables and DAOH365. SETTING: An academic tertiary referral center. PARTICIPANTS: A total of 235 heart transplant patients were included-103 MCS as a bridge to transplant patients, and 132 direct orthotopic heart transplants without prior MCS. MEASUREMENTS AND MAIN RESULTS: The median DAOH365 for the entire cohort was 348 days (IQR 335.0-354.0). There was no difference in DAOH365 between the MCS patients and patients without MCS (347.0 days [IQR 336.0-353.0] v 348.0 days [IQR 334.0-354.0], p = 0.43). Multivariate analysis identified patients who underwent a transplant after the 2018 heart transplant allocation change, pretransplant pulmonary hypertension, and increased total ischemic time as predictors of reduced DAOH365. CONCLUSIONS: In this analysis of patients undergoing orthotopic heart transplantation, there was no significant difference in DAOH365 in patients with prior MCS as a bridge to transplant compared to those without MCS. Incorporating days alive and out of the hospital into the pre-transplant evaluation may improve understanding and conceptualization of the post-transplantation patient experience and aid in shared decision-making with clinicians.

Evolution of Pain Control for Adult Pectus Excavatum Repair.

BACKGROUND: Pain control after minimally invasive repair of pectus excavatum (MIRPE) can be challenging, especially in adult patients undergoing surgical repair. This study reviewed different analgesic modalities used over ≥10 years after pectus repair. METHODS: A retrospective analysis was performed of adult patients (≥18 years) who underwent uncomplicated primary MIRPE at a single institution from October 2010 to December 2021. Patients were classified by analgesic modality used: epidural, elastomeric continuous infusion subcutaneous catheters (SC-Caths), and intercostal nerve cryoablation. Comparisons among the 3 groups were performed. RESULTS: In total, 729 patients were included (mean age, 30.9 ±10.3 years; 67% male; mean Haller index, 4.9 ±3.0). Patients in the cryoablation group required significantly lower doses of morphine equivalents (P < .001) and had overall the shortest hospital stay (mean, 1.9 ±1.5 days; P < .001) with <17% staying >2 days (vs epidural at 94% and SC-Cath at 48%; P < .001). The cryoablation group had a lower incidence of ileus and constipation (P < .001) but a higher incidence of pleural effusion requiring thoracentesis (P = .024). Mean pain scores among groups were minor (<3), and differences were insignificant. CONCLUSIONS: The use of cryoablation in conjunction with enhanced recovery pathways provided significant benefit to our patients undergoing MIRPE compared with previous analgesic modalities. These benefits included a decrease in length of hospital stay, a reduction of in-hospital opioid use, and a lower incidence of opioid-related complications associated with constipation and ileus. Further studies to assess additional potential benefits with long-term follow-up after discharge are warranted.

Update on guidelines and recommendations for enhanced recovery after thoracic surgery.

PURPOSE OF REVIEW: Enhanced recovery after thoracic surgery (ERATS) has continued its growth in popularity over the past few years, and evidence for its utility is catching up to other specialties. This review will present and examine some of that accumulated evidence since guidelines sponsored by the Enhanced Recovery after Surgery (ERAS) Society and the European Society of Thoracic Surgeons (ESTS) were first published in 2019. RECENT FINDINGS: The ERAS/ESTS guidelines published in 2019 have not been updated, but new studies have been done and new data has been published regarding some of the individual components of the guidelines as they relate to thoracic and lung resection surgery. While there is still not a consensus on many of these issues, the volume of available evidence is becoming more robust, some of which will be incorporated into this review. SUMMARY: The continued accumulation of data and evidence for the benefits of enhanced recovery techniques in thoracic and lung resection surgery will provide the thoracic anesthesiologist with guidance on how to best care for these patients before, during, and after surgery. The data from these studies will also help to elucidate which components of ERAS protocols are the most beneficial, and which components perhaps do not provide as much benefit as previously thought.

Gigantic animal cells suggest organellar scaling mechanisms across a 50-fold range in cell volume.

The largest cells are orders of magnitude bigger than the smallest cells. Organelle content scales to maintain cell function, with different organelles increasing in volume, length, or number as cells increase in size. Scaling may also reflect functional demands placed on organelles by increased cell size. Amphibians exhibit exceptional diversity in cell size. Using transmission electron microscopy, we analyzed 3 species whose enterocyte cell volumes range from 228 to 10,593 µm3. We show that nuclear volume increases by an increase in radius while mitochondrial volume increases by an increase in total network length; the endoplasmic reticulum and Golgi apparatus, with their complex shapes, are intermediate. Notably, all 4 organelle types increase in total volume proportional to cell volume, despite variation in functional (i.e., metabolic, transport) demands. This pattern suggests that organellar building blocks are incorporated into more or larger organelles following the same rules across species that vary ~50-fold in cell sizes, consistent with a "limited precursor" model for organellar scaling that, in turn, assumes equivalent cytoplasmic concentrations of organellar building block proteins. Taken together, our results lead us to hypothesize that salamanders have evolved increased biosynthetic capacity to maintain functional protein concentrations despite huge cell volumes.

The Development, Optimization, and Validation of Four Different Machine Learning Algorithms to Identify Ventilator Dyssynchrony.

Invasive mechanical ventilation can worsen lung injury. Ventilator dyssynchrony (VD) may propagate ventilator-induced lung injury (VILI) and is challenging to detect and systematically monitor because each patient takes approximately 25,000 breaths a day yet some types of VD are rare, accounting for less than 1% of all breaths. Therefore, we sought to develop and validate accurate machine learning (ML) algorithms to detect multiple types of VD by leveraging esophageal pressure waveform data to quantify patient effort with airway pressure, flow, and volume data generated during mechanical ventilation, building a computational pipeline to facilitate the study of VD. Materials and Methods: We collected ventilator waveform and esophageal pressure data from 30 patients admitted to the ICU. Esophageal pressure allows the measurement of transpulmonary pressure and patient effort. Waveform data were cleaned, features considered essential to VD detection were calculated, and a set of 10,000 breaths were manually labeled. Four ML algorithms were trained to classify each type of VD: logistic regression, support vector classification, random forest, and XGBoost. Results: We trained ML models to detect different families and seven types of VD with high sensitivity (>90% and >80%, respectively). Three types of VD remained difficult for ML to classify because of their rarity and lack of sample size. XGBoost classified breaths with increased specificity compared to other ML algorithms. Discussion: We developed ML models to detect multiple types of VD accurately. The ability to accurately detect multiple VD types addresses one of the significant limitations in understanding the role of VD in affecting patient outcomes. Conclusion: ML models identify multiple types of VD by utilizing esophageal pressure data and airway pressure, flow, and volume waveforms. The development of such computational pipelines will facilitate the identification of VD in a scalable fashion, allowing for the systematic study of VD and its impact on patient outcomes.

Lung and Heart Biology of the Dp16 Mouse Model of down Syndrome: Implications for Studying Cardiopulmonary Disease.

(1) Background: We sought to investigate the baseline lung and heart biology of the Dp16 mouse model of Down syndrome (DS) as a prelude to the investigation of recurrent respiratory tract infection. (2) Methods: In controls vs. Dp16 mice, we compared peripheral blood cell and plasma analytes. We examined baseline gene expression in lungs and hearts for key parameters related to susceptibility of lung infection. We investigated lung and heart protein expression and performed lung morphometry. Finally, and for the first time each in a model of DS, we performed pulmonary function testing and a hemodynamic assessment of cardiac function. (3) Results: Dp16 mice circulate unique blood plasma cytokines and chemokines. Dp16 mouse lungs over-express the mRNA of triplicated genes, but not necessarily corresponding proteins. We found a sex-specific decrease in the protein expression of interferon α receptors, yet an increased signal transducer and activator of transcription (STAT)-3 and phospho-STAT3. Platelet-activating factor receptor protein was not elevated in Dp16 mice. The lungs of Dp16 mice showed increased stiffness and mean linear intercept and contained bronchus-associated lymphoid tissue. The heart ventricles of Dp16 mice displayed hypotonicity. Finally, Dp16 mice required more ketamine to achieve an anesthetized state. (4) Conclusions: The Dp16 mouse model of DS displays key aspects of lung heart biology akin to people with DS. As such, it has the potential to be an extremely valuable model of recurrent severe respiratory tract infection in DS.

CNP-miR146a Decreases Inflammation in Murine Acute Infectious Lung Injury.

Acute respiratory distress syndrome (ARDS) has approximately 40% in-hospital mortality, and treatment is limited to supportive care. Pneumonia is the underlying etiology in many cases with unrestrained inflammation central to the pathophysiology. We have previously shown that CNP-miR146a, a radical scavenging cerium oxide nanoparticle (CNP) conjugated to the anti-inflammatory microRNA(miR)-146a, reduces bleomycin- and endotoxin-induced acute lung injury (ALI) by decreasing inflammation. We therefore hypothesized that CNP-miR146a would decrease inflammation in murine infectious ALI. Mice were injured with intratracheal (IT) MRSA or saline followed by treatment with IT CNP-miR146a or saline control. Twenty-four hours post-infection, bronchoalveolar lavage fluid (BALF) and whole lungs were analyzed for various markers of inflammation. Compared to controls, MRSA infection significantly increased proinflammatory gene expression (IL-6, IL-8, TNFα, IL-1ß; p < 0.05), BALF proinflammatory cytokines (IL-6, IL-8, TNFα, IL-1ß; p < 0.01), and inflammatory cell infiltrate (p = 0.03). CNP-miR146a treatment significantly decreased proinflammatory gene expression (IL-6, IL-8, TNFα, IL-1ß; p < 0.05), bronchoalveolar proinflammatory protein leak (IL-6, IL-8, TNFα; p < 0.05), and inflammatory infiltrate (p = 0.01). CNP-miR146a decreases inflammation and improves alveolar-capillary barrier integrity in the MRSA-infected lung and has significant promise as a potential therapeutic for ARDS.

Modeling Ventilator-Induced Lung Injury and Neutrophil Infiltration to Infer Injury Interdependence.

Acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI) are heterogeneous conditions. The spatiotemporal evolution of these heterogeneities is complex, and it is difficult to elucidate the mechanisms driving its progression. Through previous quantitative analyses, we explored the distributions of cellular injury and neutrophil infiltration in experimental VILI and discovered that VILI progression is characterized by both the formation of new injury in quasi-random locations and the expansion of existing injury clusters. Distributions of neutrophil infiltration do not correlate with cell injury progression and suggest a systemic response. To further examine the dynamics of VILI, we have developed a novel computational model that simulates damage (cellular injury progression and neutrophil infiltration) using a stochastic approach. Optimization of the model parameters to fit experimental data reveals that the range and strength of interdependence between existing and new damaged regions both increase as mechanical ventilation patterns become more injurious. The interdependence of cellular injury can be attributed to mechanical tethering forces, while the interdependence of neutrophils is likely due to longer-range cell signaling pathways.