Extracellular vesicles in acute respiratory distress syndrome: Understanding protective and harmful signaling for the development of new therapeutics.

Acute respiratory distress syndrome (ARDS) is a severe respiratory condition characterized by increased lung permeability, hyper-inflammatory state, and fluid leak into the alveolar spaces. ARDS is a heterogeneous disease, with multiple direct and indirect causes that result in a mortality of up to 40%. Due to the ongoing Covid-19 pandemic, its incidence has increased up to ten-fold. Extracellular vesicles (EVs) are small liposome-like particles that mediate intercellular communication and play a major role in ARDS pathophysiology. Indeed, they participate in endothelial barrier dysfunction and permeability, neutrophil, and macrophage activation, and also in the development of a hypercoagulable state. A more thorough understanding of the variegated and cell-specific functions of EVs may lead to the development of safe and effective therapeutics. In this review, we have collected evidence of EVs role in ARDS, revise the main mechanisms of production and internalization and summarize the current therapeutical approaches that have shown the ability to modulate EV signaling.

Exploring the influence of behavioral factors on depression and anxiety scores during the COVID-19 pandemic: insights from the Virginia statewide COVIDsmart longitudinal study.

BACKGROUND: Amidst the COVID-19 pandemic, there has been growing concern about the declining mental health and healthy behaviors compared to pre-pandemic levels. Despite this, there is a lack of longitudinal studies that have examined the relationship between health behaviors and mental health during the pandemic. In response, the statewide COVIDsmart longitudinal study was launched. The study's main objective is to better understand the effects of the pandemic on mental health. Findings may provide a foundation for the identification of public health strategies to mitigate future negative impacts of the pandemic. METHODS: Following online recruitment in spring of 2021, adults, ages 18 to 87, filled out social, mental, economic, occupational, and physical health questionnaires on the digital COVIDsmart platform at baseline and through six monthly follow-ups. Changes in the participant's four health behaviors (e.g., tobacco and alcohol consumption, physical activity, and social media use), along with sex, age, loneliness score, and reported social and economic (SE) hardships, were analyzed for within-between group associations with depression and anxiety scores using Mixed Models Repeated Measures. RESULTS: In this study, of the 669 individuals who reported, the within-between group analysis indicated that younger adults (F = 23.81, p < 0.0001), loneliness (F = 234.60, p < 0.0001), SE hardships (F = 31.25, p < 0.0001), increased tobacco use (F = 3.05, p = 0.036), decreased physical activity (F = 6.88, p = 0.0002), and both positive and negative changes in social media use (F = 7.22, p = 0.0001) were significantly associated with worse depression scores. Additionally, females (F = 6.01, p = 0.015), younger adults (F = 32.30, p < 0.0001), loneliness (F = 154.59, p < 0.0001), SE hardships (F = 22.13, p < 0.0001), increased tobacco use (F = 4.87, p = 0.004), and both positive and negative changes in social media use (F = 3.51, p = 0.016) were significantly associated with worse anxiety scores. However, no significant changes were observed in the within-between group measurements of depression and anxiety scores over time (p > 0.05). Physical activity was not associated with anxiety nor was alcohol consumption with both depression and anxiety (p > 0.05). CONCLUSIONS: This study demonstrates the longitudinal changes in behaviors within the context of the COVID-19 pandemic. These findings may facilitate the design of preventative population-based health approaches during the COVID-19 pandemic or future pandemics.

A Digital Health Initiative (COVIDsmart) for Remote Data Collection and Study of COVID-19's Impact on the State of Virginia: Prospective Cohort Study.

BACKGROUND: The COVID-19 pandemic has affected people's lives beyond severe and long-term physical health symptoms. Social distancing and quarantine have led to adverse mental health outcomes. COVID-19-induced economic setbacks have also likely exacerbated the psychological distress affecting broader aspects of physical and mental well-being. Remote digital health studies can provide information about the pandemic's socioeconomic, mental, and physical impact. COVIDsmart was a collaborative effort to deploy a complex digital health research study to understand the impact of the pandemic on diverse populations. We describe how digital tools were used to capture the effects of the pandemic on the overall well-being of diverse communities across large geographical areas within the state of Virginia. OBJECTIVE: The aim is to describe the digital recruitment strategies and data collection tools applied in the COVIDsmart study and share the preliminary study results. METHODS: COVIDsmart conducted digital recruitment, e-Consent, and survey collection through a Health Insurance Portability and Accountability Act-compliant digital health platform. This is an alternative to the traditional in-person recruitment and onboarding method used for studies. Participants in Virginia were actively recruited over 3 months using widespread digital marketing strategies. Six months of data were collected remotely on participant demographics, COVID-19 clinical parameters, health perceptions, mental and physical health, resilience, vaccination status, education or work functioning, social or family functioning, and economic impact. Data were collected using validated questionnaires or surveys, completed in a cyclical fashion and reviewed by an expert panel. To retain a high level of engagement throughout the study, participants were incentivized to stay enrolled and complete more surveys to further their chances of receiving a monthly gift card and one of multiple grand prizes. RESULTS: Virtual recruitment demonstrated relatively high rates of interest in Virginia (N=3737), and 782 (21.1%) consented to participate in the study. The most successful recruitment technique was the effective use of newsletters or emails (n=326, 41.7%). The primary reason for contributing as a study participant was advancing research (n=625, 79.9%), followed by the need to give back to their community (n=507, 64.8%). Incentives were only reported as a reason among 21% (n=164) of the consented participants. Overall, the primary reason for contributing as a study participant was attributed to altruism at 88.6% (n=693). CONCLUSIONS: The COVID-19 pandemic has accelerated the need for digital transformation in research. COVIDsmart is a statewide prospective cohort to study the impact of COVID-19 on Virginians' social, physical, and mental health. The study design, project management, and collaborative efforts led to the development of effective digital recruitment, enrollment, and data collection strategies to evaluate the pandemic's effects on a large, diverse population. These findings may inform effective recruitment techniques across diverse communities and participants' interest in remote digital health studies.

Nodular granulomatous Pneumocystis jiroveci pneumonia consequent to delayed immune reconstitution inflammatory syndrome.

Although Pneumocystis jiroveci pneumonia (PCP) is a frequent manifestation of acquired immune deficiency syndrome (AIDS), the granulomatous form is uncommon. Here, we present an unusual case of granulomatous PCP consequent to immune reconstitution inflammatory syndrome (IRIS) after highly active antiretroviral therapy. A 36-year-old woman with human immunodeficiency virus (HIV) presented with cough and dyspnea that were attributed to typical PCP associated with AIDS. She was successfully treated with antibiotic, steroid, and antiretroviral therapies. After six months, however, she presented with consolidating lung lesions caused by bronchial obstruction from PCP granulomatous disease. Although antibiotics were ineffective, the effectiveness of steroid therapy suggested a diagnosis of granulomatous IRIS caused by persistent PCP antigens. Physicians should strongly suspect PCP in HIV-positive patients with nodular lung lesions and must remain aware that these lesions, if immune in origin, might not respond to antimicrobial therapy.

Inhaled TRIM72 Protein Protects Ventilation Injury to the Lung through Injury-guided Cell Repair.

Studies showed that TRIM72 is essential for repair of alveolar cell membrane disruptions, and exogenous recombinant human TRIM72 protein (rhT72) demonstrated tissue-mending properties in animal models of tissue injury. Here we examine the mechanisms of rhT72-mediated lung cell protection in vitro and test the efficacy of inhaled rhT72 in reducing tissue pathology in a mouse model of ventilator-induced lung injury. In vitro lung cell injury was induced by glass beads and stretching. Ventilator-induced lung injury was modeled by injurious ventilation at 30 ml/kg tidal volume. Affinity-purified rhT72 or control proteins were added into culture medium or applied through nebulization. Cellular uptake and in vivo distribution of rhT72 were detected by imaging and immunostaining. Exogenous rhT72 maintains membrane integrity of alveolar epithelial cells subjected to glass bead injury in a dose-dependent manner. Inhaled rhT72 decreases the number of fatally injured alveolar cells, and ameliorates tissue-damaging indicators and cell injury markers after injurious ventilation. Using in vitro stretching assays, we reveal that rhT72 improves both cellular resilience to membrane wounding and membrane repair after injury. Image analysis detected rhT72 uptake by rat alveolar epithelial cells, which can be inhibited by a cholesterol-disrupting agent. In addition, inhaled rhT72 distributes to the distal lungs, where it colocalizes with phosphatidylserine detection on nonpermeabilized lung slices to label wounded cells. In conclusion, our study showed that inhaled rhT72 accumulates in injured lungs and protects lung tissue from ventilator injury, the mechanisms of which include improving cell resilience to membrane wounding, localizing to injured membrane, and augmenting membrane repair.

Inhibition of Macrophage Complement Receptor CRIg by TRIM72 Polarizes Innate Immunity of the Lung.

The complement system plays a critical role in immune responses against pathogens. However, its identity and regulation in the lung are not fully understood. This study aimed to explore the role of tripartite motif protein (TRIM) 72 in regulating complement receptor (CR) of the Ig superfamily (CRIg) in alveolar macrophage (AM) and innate immunity of the lung. Imaging, absorbance quantification, and flow cytometry were used to evaluate in vitro and in vivo AM phagocytosis with normal, or altered, TRIM72 expression. Pulldown, coimmunoprecipitation, and gradient binding assays were applied to examine TRIM72 and CRIg interaction. A pneumonia model was established by intratracheal injection of Pseudomonas aeruginosa. Mortality, lung bacterial burden, and cytokine levels in BAL fluid and lung tissues were examined. Our data show that TRIM72 inhibited CR-mediated phagocytosis, and release of TRIM72 inhibition led to increased AM phagocytosis. Biochemical assays identified CRIg as a binding partner of TRIM72, and TRIM72 inhibited formation of the CRIg-phagosome. Genetic ablation of TRIM72 led to improved pathogen clearance, reduced cytokine storm, and improved survival in murine models of severe pneumonia, specificity of which was confirmed by adoptive transfer of wild-type or TRIM72KO AMs to AM-depleted TRIM72KO mice. TRIM72 overexpression promoted bacteria-induced NF-κB activation in murine alveolar macrophage cells. Our data revealed a quiescent, noninflammatory bacterial clearance mechanism in the lung via AM CRIg, which is suppressed by TRIM72. In vivo data suggest that targeted suppression of TRIM72 in AM may be an effective measure to treat fatal pulmonary bacterial infections.

The implementation of a multinational "walking blood bank" in a combat zone: The experience of a health service team deployed to a medical treatment facility in Afghanistan.

BACKGROUND: We present here a description of the experience in whole-blood transfusion of a health service team deployed to a medical treatment facility in Afghanistan from June 2011 to October 2011. The aim of our work was to show how a "walking blood bank" could provide a sufficient supply. METHODS: We gathered the blood-group types of military personnel deployed to the theater of operations to evaluate our "potential walking blood bank," and we compared these data with our needs. RESULTS: Blood type frequencies among our "potential walking blood bank" were similar to those observed in European or American countries. Our resources could have been limited because of a low frequency of B blood type and negative rhesus in our "potential walking blood bank." Because of the large number of potential donors in the theater of operations, the risk of blood shortage was quite low and we did not face blood shortage despite significant transfusion requirements. Actually, 93 blood bags were collected, including rare blood types like AB and B blood types. CONCLUSION: In our experience, this international "walking blood bank" provided a quick, safe, and sufficient blood supply. More research in this area is needed, and our results should be confirmed by further prospective trials. LEVEL OF EVIDENCE: Therapeutic study, level V.

Cardiopulmonary exercise test interpretation using age-matched controls to evaluate exertional dyspnea.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is one method to diagnose unexplained dyspnea in young adults, yet few normal reference values exist in this population. This study evaluated interpretation of maximal CPET in a young adult cohort with known pulmonary disorders using published reference values compared to age-matched normal controls. METHODS: A control population of 69 healthy military volunteers with normal chest radiographs, pulmonary function testing, and bronchoprovocation testing were compared to 105 patients with exertional dyspnea. Both groups underwent a standardized evaluation including CPET on a graded exercise treadmill to maximal exercise with expired gas analysis. RESULTS: Measurements from CPET in the dyspnea group were interpreted using published reference values compared to control population results (mean +/- 1.65 x SD). Statistical comparison of predicted normals (reference vs. control) of maximal oxygen consumption (> 83% vs. 82%), ventilatory anaerobic threshold (> 40% vs. 53%), respiratory rate (< 60 vs. 56 breaths/min), tidal volume to inspiratory capacity (< 80% vs. 111%), ventilatory equivalent for carbon dioxide production (< 40 vs. 38), and maximal voluntary ventilation minus minute ventilation (> 11 vs. -1 L/min) was performed. The overall specificity for tidal volume to inspiratory capacity improved using age-matched controls but sensitivity was decreased. Other parameters were not significantly different. CONCLUSIONS: The use of age-matched controls for CPET results in an increase in specificity and decrease in sensitivity for respiratory limitations to exercise, when compared to reference values. The study findings suggest that CPET may be insensitive in detecting mild disease in young healthy adults.

Inspiratory flow-volume curve evaluation for detecting upper airway disease.

BACKGROUND: The 2005 American Thoracic Society/European Respiratory Society guidelines on spirometry emphasize examination of the inspiratory curve of the flow-volume loop for evidence of intrathoracic or extrathoracic upper airway obstruction. We sought to determine how frequently evaluations are performed for abnormal inspiratory curves. METHODS: We retrospectively reviewed all examinations performed in our pulmonary function testing laboratory over a 12-month period (n = 2,662). In patients with normal spirometry or a mild restrictive defect, we inspected the inspiratory curves for truncation, flattening, or absent loop. With patients who had an abnormal inspiratory curve, we examined 3 flow-volume loops to determine if more than one loop showed an inspiratory abnormality, and to assess changes in the mid-flow ratio (ratio of forced expiratory flow at 50% of the forced expiratory volume to forced inspiratory flow at 50% of the forced inspiratory volume), and we used the loop that had the best inspiratory and expiratory curves. We reviewed the medical records for underlying disease processes and evidence of upper airway evaluation. RESULTS: One hundred twenty-three patients (4.6%) had an abnormal inspiratory curve. Sixty-nine (56%) of those 123 patients had inspiratory abnormalities on > 2 flow-volume loops. Evaluation of the inspiratory abnormality was undertaken in only 17% of all patients, and 30% of patients who had consistently abnormal inspiratory curves. A specific etiology was identified in 52% of the evaluated patients. Vocal cord dysfunction was the most frequent diagnosis. Utilizing the loop that had the combination of the best inspiratory and expiratory curves decreased the mid-flow ratio from 3.07 +/- 1.63 to 1.77 +/- 1.15. CONCLUSIONS: An abnormal inspiratory curve in the presence of otherwise normal spirometry should prompt an evaluation for the etiology. If one of the flow-volume inspiratory curves shows an abnormality, all the inspiratory curves from that PFT session should be reviewed, and if more than one inspiratory curves is abnormal, both anatomical and functional evaluation should be undertaken for intrathoracic and extrathoracic upper airway obstruction.

Use of a high-flow oxygen delivery system in a critically ill patient with dementia.

We used a high-flow nasal cannula with a patient who required a high fraction of inspired oxygen but could not tolerate a nasal or facial mask. We saw a 92-year-old woman with delirium and dementia in the intensive care unit for multi-lobar pneumonia with severe hypoxemia. Attempts to oxygenate the patient failed because she was unable to tolerate various facial and nasal masks. We then tried a high-flow nasal cannula (Vapotherm 2000i), which she tolerated well, and she had marked improvement in gas exchange and quality of life. The patient had severe health-care-associated pneumonia, accompanied by delirium and hypoxemia. It became apparent that the patient's death was imminent, and the goal of therapy was palliative. She had previously clearly expressed a desire not to undergo intubation and mechanical ventilation. In a situation where the patient was agitated and unable to tolerate a mask, the high-flow cannula reduced her agitation and improved her dyspnea, oxygenation, tolerance of oxygen therapy, and comfort at the end of life. Oxygen via high-flow cannula may enhance quality of life by reducing hypoxemia in patients who are unable to tolerate a mask but need a high oxygen concentration.