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Since the first reported success of lung transplantation over three decades ago, chronic allograft rejection has carried the highest burden of long-term mortality. [...]this study may have a great clinical impact because it introduces the possibility of inhibiting the RAS/MEK/ERK pathway, using agents such as trametinib, after lung transplantation to suppress indirect allorecognition and reduce the incidence of chronic rejection. [...]replacement of calcineurin inhibitors with a drug such as trametinib in human lung transplant recipients may lead to acute allograft rejection even at late time points after transplantation, assuming that its mechanism of action is suppression of indirect allorecognition. [...]early introduction of MEK inhibitors may ameliorate both ischemia-reperfusion injury and chronic rejection.

Capabilities in continuous monitoring of key physiological parameters of disease have never been more important than in the context of the global COVID-19 pandemic. Soft, skin-mounted electronics that incorporate high-bandwidth, miniaturized motion sensors enable digital, wireless measurements of mechanoacoustic (MA) signatures of both core vital signs (heart rate, respiratory rate, and temperature) and underexplored biomarkers (coughing count) with high fidelity and immunity to ambient noises. This paper summarizes an effort that integrates such MA sensors with a cloud data infrastructure and a set of analytics approaches based on digital filtering and convolutional neural networks for monitoring of COVID-19 infections in sick and healthy individuals in the hospital and the home. Unique features are in quantitative measurements of coughing and other vocal events, as indicators of both disease and infectiousness. Systematic imaging studies demonstrate correlations between the time and intensity of coughing, speaking, and laughing and the total droplet production, as an approximate indicator of the probability for disease spread. The sensors, deployed on COVID-19 patients along with healthy controls in both inpatient and home settings, record coughing frequency and intensity continuously, along with a collection of other biometrics. The results indicate a decaying trend of coughing frequency and intensity through the course of disease recovery, but with wide variations across patient populations. The methodology creates opportunities to study patterns in biometrics across individuals and among different demographic groups.

Background Lung transplantation for situs inverse is considered technically challenging because of the reverse positioning of the organs. By providing a detailed description of the surgical procedure, perioperative care, and post-transplant follow-up, we aim to contribute valuable information to the existing knowledge base. We presented two cases of successful bilateral sequential lung transplantation in situs inverse patients. Case presentation Our first patient was a 28-year-old, non-smoking woman with Kartagener syndrome and advanced bronchiectasis that developed into pneumonia and required repeated hospital admissions. She underwent double lung transplantation. During the lung transplant procedure, venoarterial extracorporeal membrane oxygenation (VA ECMO) support was provided. The recipient’s morphologically right (anatomically left) lung was explanted. The right main bronchus was anastomosed, followed by the pulmonary artery and left atrial anastomoses. Afterward, we proceeded with the left side. Similar to the right side, left pneumonectomy and implantation were performed using the same methods. The duration of VA ECMO support was 147 min with a 328-min ischemic time. Because of the significant size mismatch, nonanatomic lung volume reduction over the right middle and left upper lobes was necessary. The patient had no complications postoperatively and was discharged on post-operative day (POD) 12. Our second patient was a 51-year- old man with scleroderma-associated interstitial lung disease with situs inversus. Bilateral sequential lung transplantation was performed. Similar to case 1, a clamshell incision was made at the fourth intercostal space entry. The patient then received VA ECMO support identical to that in case 1. The total VA ECMO support time was 155 min with 295 min of ischemic time. The patient recovered uneventfully and was discharged on POD 13. Conclusions Lung transplantation for situs inverse can be a viable treatment option without modifying established transplantation procedures.

A 73-year-old woman presented with recurrent tracheoesophageal fistula (TEF; Figure 1A), leading to aspiration pneumonitis (Figure 1B), malnutrition, and sepsis, 3 years after surgical repair of an iatrogenic TEF sustained during a carotid endarterectomy. Because of the patient’s severe debilitation and prior neck operations, the risks of surgical repair were prohibitive. [...]a staged minimally invasive bronchoendoscopic approach was developed. Anthony B. Mozer 1, Eriberto Michel 1, Colin Gillespie 1, 2, and Ankit Bharat 1, 2 1Division of Thoracic Surgery, Department of Surgery, and 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Using these markers we also observed heterogeneity in the alveolar macrophage population, which may reflect the relative contribution of monocyte-derived versus tissue-resident cells to the alveolar macrophage pool. Because this panel relies exclusively on the identification of cell surface markers, it is appropriate for sorting and recovering live cells for subsequent analysis. CD 163 is a scavenger receptor for hemoglobin/haptoglobin complex highly expressed on tissue macrophages, and it has been proposed as a marker of \"resolving\" monocyte-derived macrophages (10, 11). Because our previous studies in a mouse model of lung fibrosis demonstrated that differential expression of Siglec F allows discrimination of the tissue-resident and monocyte-derived macrophages (8), we now speculate that the heterogeneity in CD 163 expression in human alveolar macrophages may also reflect their differential ontogeny.

Primary graft dysfunction (PGD) is the leading cause of postoperative mortality in lung transplant recipients and the most important risk factor for development of chronic lung allograft dysfunction. The mechanistic basis for the variability in the incidence and severity of PGD between lung transplant recipients is not known. Using a murine orthotopic vascularized lung transplant model, we found that redundant activation of Toll-like receptors 2 and 4 (TLR2 and -4) on nonclassical monocytes activates MyD88, inducing the release of the neutrophil attractant chemokine CXCL2. Deletion of Itgam (encodes CD11b) in nonclassical monocytes enhanced their production of CXCL2 and worsened PGD, while a CD11b agonist, leukadherin-1, administered only to the donor lung prior to lung transplantation, abrogated CXCL2 production and PGD. The damage-associated molecular pattern molecule HMGB1 was increased in peripheral blood samples from patients undergoing lung transplantation after reperfusion and induced CXCL2 production in nonclassical monocytes via TLR4/MyD88. An inhibitor of HMGB1 administered to the donor and recipient prior to lung transplantation attenuated PGD. Our findings suggest that CD11b acts as a molecular brake to prevent neutrophil recruitment by nonclassical monocytes following lung transplantation, revealing an attractive therapeutic target in the donor lung to prevent PGD in lung transplant recipients.

Chronic diseases that result in end-stage organ damage cause inflammation, which can reveal sequestered self-antigens (SAgs) in that organ and trigger autoimmunity. The thymus gland deletes self-reactive T-cells against ubiquitously expressed SAgs, while regulatory mechanisms in the periphery control immune responses to tissue-restricted SAgs. It is now established that T-cells reactive to SAgs present in certain organs (e.g., lungs, pancreas, and intestine) are incompletely eliminated, and the dysregulation of peripheral immuneregulation can generate immune responses to SAgs. Therefore, chronic diseases can activate self-reactive lymphocytes, inducing tissue-restricted autoimmunity. During organ transplantation, donor lymphocytes are tested against recipient serum (i.e., cross-matching) to detect antibodies (Abs) against donor human leukocyte antigens, which has been shown to reduce Ab-mediated hyperacute rejection. However, primary allograft dysfunction and rejection still occur frequently. Because donor lymphocytes do not express tissue-restricted SAgs, preexisting Abs against SAgs are undetectable during conventional cross-matching. Preexisting and de novo immune responses to tissue-restricted SAgs (i.e., autoimmunity) play a major role in rejection. In this review, we discuss the evidence that supports autoimmunity as a contributor to rejection. Testing for preexisting and de novo immune responses to tissue-restricted SAgs and treatment based on immune responses after organ transplantation may improve short- and long-term outcomes after transplantation.

Supranucleosomal chromatin structure, including chromatin domain conformation, is involved in the regulation of gene expression and its dysregulation has been associated with carcinogenesis. Prior studies have shown that cells in the buccal mucosa carry a molecular signature of lung cancer among the cigarette-smoking population, the phenomenon known as field carcinogenesis or field of injury. Thus, we hypothesized that chromatin structural changes in buccal mucosa can be predictive of lung cancer. However, the small size of the chromatin chain (approximately 20 nm) folded into chromatin packing domains, themselves typically below 300 nm in diameter, preclude the detection of alterations in intradomain chromatin conformation using diffraction-limited optical microscopy. In this study, we developed an optical spectroscopic statistical nanosensing technique to detect chromatin packing domain changes in buccal mucosa as a lung cancer biomarker: chromatin-sensitive partial wave spectroscopic microscopy (csPWS). Artificial intelligence (AI) was applied to csPWS measurements of chromatin alterations to enhance diagnostic performance. Our AI-enhanced buccal csPWS nanocytology of 179 patients at two clinical sites distinguished Stage-I lung cancer versus cancer-free controls with an area under the ROC curve (AUC) of 0.92 ± 0.06 for Site 1 (in-state location) and 0.82 ± 0.11 for Site 2 (out-of-state location).

There have been over 769 million cases of COVID-19, and up to 50% of infected individuals are asymptomatic. The purpose of this study aimed to assess the use of a clinical-grade physiological wearable monitoring system, ANNE One, to develop an artificial intelligence algorithm for (1) cough detection and (2) early detection of COVID-19, through the retrospective analysis of prospectively collected physiological data from longitudinal wear of ANNE sensors in a multicenter single arm study of subjects at high risk for COVID-19 due to occupational or home exposures. The study employed a two-fold approach: cough detection algorithm development and COVID-19 detection algorithm development. For cough detection, healthy individuals wore an ANNE One chest sensor during scripted activity. The final performance of the algorithm achieved an F-1 score of 83.3% in twenty-seven healthy subjects during biomarker validation. In the COVID-19 detection algorithm, individuals at high-risk for developing COVID-19 because of recent exposures received ANNE One sensors and completed daily symptom surveys. An algorithm analyzing vital parameters (heart rate, respiratory rate, cough count, etc.) for early COVID-19 detection was developed. The COVID-19 detection algorithm exhibited a sensitivity of 0.47 and specificity of 0.72 for detecting COVID-19 in 325 individuals with recent exposures. Participants demonstrated high adherence (≥ 4 days of wear per week). ANNE One shows promise for detection of COVID-19. Inclusion of respiratory biomarkers (e.g., cough count) enhanced the algorithm's predictive ability. These findings highlight the potential value of wearable devices in early disease detection and monitoring.

Ischemia/reperfusion injury-mediated (IRI-mediated) primary graft dysfunction (PGD) adversely affects both short- and long-term outcomes after lung transplantation, a procedure that remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrated by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observed that lung-infiltrating B cells produce the monocyte chemokine CCL7 in a TLR4-TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We found that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborated our findings in reperfused human lungs, in which we observed a correlation between B cell infiltration and CM recruitment after transplantation. This study describes a role for B cells as critical orchestrators of lung IRI. As B cells can be depleted with currently available agents, our study provides a rationale for clinical trials investigating B cell-targeting therapies.