Hemorrhage, Disseminated Intravascular Coagulopathy, and Thrombosis Complications Among Critically Ill Patients with COVID-19: An International COVID-19 Critical Care Consortium Study.

OBJECTIVES: To determine the prevalence and outcomes associated with hemorrhage, disseminated intravascular coagulopathy, and thrombosis (HECTOR) complications in ICU patients with COVID-19. DESIGN: Prospective, observational study. SETTING: Two hundred twenty-nine ICUs across 32 countries. PATIENTS: Adult patients (≥ 16 yr) admitted to participating ICUs for severe COVID-19 from January 1, 2020, to December 31, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: HECTOR complications occurred in 1,732 of 11,969 study eligible patients (14%). Acute thrombosis occurred in 1,249 patients (10%), including 712 (57%) with pulmonary embolism, 413 (33%) with myocardial ischemia, 93 (7.4%) with deep vein thrombosis, and 49 (3.9%) with ischemic strokes. Hemorrhagic complications were reported in 579 patients (4.8%), including 276 (48%) with gastrointestinal hemorrhage, 83 (14%) with hemorrhagic stroke, 77 (13%) with pulmonary hemorrhage, and 68 (12%) with hemorrhage associated with extracorporeal membrane oxygenation (ECMO) cannula site. Disseminated intravascular coagulation occurred in 11 patients (0.09%). Univariate analysis showed that diabetes, cardiac and kidney diseases, and ECMO use were risk factors for HECTOR. Among survivors, ICU stay was longer (median days 19 vs 12; p < 0.001) for patients with versus without HECTOR, but the hazard of ICU mortality was similar (hazard ratio [HR] 1.01; 95% CI 0.92-1.12; p = 0.784) overall, although this hazard was identified when non-ECMO patients were considered (HR 1.13; 95% CI 1.02-1.25; p = 0.015). Hemorrhagic complications were associated with an increased hazard of ICU mortality compared to patients without HECTOR complications (HR 1.26; 95% CI 1.09-1.45; p = 0.002), whereas thrombosis complications were associated with reduced hazard (HR 0.88; 95% CI 0.79-0.99, p = 0.03). CONCLUSIONS: HECTOR events are frequent complications of severe COVID-19 in ICU patients. Patients receiving ECMO are at particular risk of hemorrhagic complications. Hemorrhagic, but not thrombotic complications, are associated with increased ICU mortality.

"Doctor" Badge Promotes Accurate Role Identification and Reduces Gender-Based Aggressions in Female Resident Physicians.

OBJECTIVE: Role misidentification among hospital staff is common. Female resident physicians are more likely to be misidentified as non-physicians. This study utilized a pre-post examination to determine if the usage of a "doctor" badge by resident physicians at a Veterans Affairs Medical Center influences role identification, gender-based aggressions, and workplace experience. METHODS: Twenty-six psychiatry residents at the Veterans Affairs Boston Healthcare System participated in a voluntary, anonymous electronic pre-survey in December 2020 and post-survey in March 2021 to report their experiences with role identification and gender-based aggressions before and after the implementation of a "doctor" badge. RESULTS: Females were significantly more likely than males to report role misidentification (x2(1)=10.8, p=0.001). Females were significantly more likely to experience gender-based aggressions compared to males (x2(1)=19.5, p<0.001). Compared to pre-intervention, females who wore the badge were significantly less likely to be misidentified (x2(1)=9.6, p=0.002). There was no significance when comparing males who were misidentified pre- to post-intervention (x2(1)=1.1, p=0.294). Compared to pre-intervention, females who wore the badge were significantly less likely to experience gender-based aggressions (x2(1)=17.3, p=<0.001). Compared to pre-intervention, there was no significant change in gender-based aggressions for males who wore the badge (x2(1)=1.05, p=0.306). CONCLUSIONS: Female residents were more likely than male residents to report role misidentification. Usage of the "doctor" badge resulted in improved role identification and a reduction in gender-based aggressions for females, but not males. "Doctor" badges can improve role identification, gender-based aggressions, workplace experience, patient communication, and care.

Functional Impact of Human Genetic Variants of COL18A1/Endostatin on Pulmonary Endothelium.

Pulmonary arterial hypertension (PAH) is an incurable disease characterized by disordered and dysfunctional angiogenesis leading to small-vessel loss and an obliterative vasculopathy. The pathogenesis of PAH is not fully understood, but multiple studies have demonstrated links between elevated angiostatic factors, disease severity, and adverse clinical outcomes. ES (endostatin), one such circulating angiostatic peptide, is the cleavage product of the proteoglycan COL18A1 (collagen α1[XVIII] chain). Elevated serum ES is associated with increased mortality and disease severity in PAH. A nonsynonymous variant of ES (aspartic acid-to-asparagine substitution at amino acid 104; p.D104N) is associated with differences in PAH survival. Although COL18A1/ES expression is markedly increased in remodeled pulmonary vessels in PAH, the impact of ES on pulmonary endothelial cell (PEC) biology and molecular contributions to PAH severity remain undetermined. In the present study, we characterized the effects of exogenous ES on human PEC biology and signaling. We demonstrated that ES inhibits PEC migration, proliferation, and cell survival, with significant differences between human variants, indicating that they are functional genetic variants. ES promotes proteasome-mediated degradation of the transcriptional repressor ID1, increasing expression and release of TSP-1 (thrombospondin 1). ES inhibits PEC migration via an ID1/TSP-1/CD36-dependent pathway, in contrast to proliferation and apoptosis, which require both CD36 and CD47. Collectively, the data implicate ES as a novel negative regulator of ID1 and an upstream propagator of an angiostatic signal cascade converging on CD36 and CD47, providing insight into the cellular and molecular effects of a functional genetic variant linked to altered outcomes in PAH.

Five-Year Mortality Hazard Is Reduced In Chronic Obstructive Pulmonary Disease Patients Receiving Double- versus Single-Lung Transplants.

BACKGROUND: Previous studies suggest double-lung transplant (DLT) may be associated with superior survival compared to single-lung transplantation (SLT) in chronic obstructive pulmonary disease (COPD) recipients. The purpose of this study was to compare survival in patients with COPD undergoing DLT versus SLT since the inception of the lung allocation score. METHODS: We used the United Network for Organ Sharing database to retrospectively identify adult patients with COPD who underwent isolated lung transplantation from 5/4/2005-12/31/2014. We then separated patients into DLT versus SLT. Short-term (1 y) and long-term survival (5 y) were compared between DLT and SLT cohorts by the method of Kaplan-Meier, and Cox proportional hazards modeling was used to adjust for case mix. RESULTS: Four thousand eight hundred thirty-two COPD patients were listed, and 3554 underwent lung transplantation over the study period, including 1358 SLTs (38%) and 2196 DLTs (62%). Survival 1 y after listing was 93% for those remaining wait listed (n = 1892) versus 91% for SLT (n = 1093) versus 89% for DLT (n = 1847) (log-rank P < 0.01). Survival at 1 y after transplant was 88% for both SLT and DLT groups (log-rank P = 0.93); however, 5-y survival was significantly lower after SLT (51% versus 59%, log-rank P < 0.01). After risk adjustment, hazard for 1-y mortality after DLT was not significantly reduced compared to SLT (hazard ratio 0.89 [0.69-1.14], P = 0.36) but was significantly reduced 5 y after DLT (hazard ratio 0.88 [0.78-0.99], P = 0.04). CONCLUSIONS: In the largest survival analysis of COPD recipients since the inception of the lung allocation score, the hazard for 5-y mortality was significantly reduced in recipients who underwent DLT as compared to SLT.

Seeing is believing: an exploration of what residents value when they receive feedback.

OBJECTIVE: The primary purpose of this paper is to report on psychiatry residents' perceptions of what is important when receiving feedback from evaluators. METHODS: In January 2018, as part of the Harvard South Shore Psychiatry Residency Training Program's (HSS) ongoing local quality improvement efforts to enhance the delivery and effectiveness of feedback that residents receive from faculty during training, the authors disseminated a survey to psychiatry residents (n = 31) at HSS. Residents rated the level of importance of 17 statements pertaining to the way feedback is delivered. Two open-ended prompts also allowed respondents to share examples of growth-oriented and unhelpful feedback they have received during residency. RESULTS: Twenty-seven residents responded (87% response rate). Eighty-one percent rated "the evaluator models the same behavior they're encouraging" as "extremely important" when receiving feedback. Many residents also rated the following survey items as "extremely important": "confidence in the evaluator's clinical and interpersonal skills" (63.0%), "amount of time the evaluator observed the resident" (51.9%), "there is a way to fix a performance deficit" (51.8%), and "specific feedback based off the resident's work" (48.1%). Conversely, only 11.1% of residents rated the feedback sandwich as "extremely important." CONCLUSIONS: Despite a small sample size, this project demonstrated that, when receiving feedback, the majority of psychiatry residents strongly value when evaluators model the targeted behavior. The feedback sandwich was least important to residents. This project underscores the importance of evaluators serving as role models in the context of feedback, and findings can be used in faculty development activities focused on feedback delivery best practices.

Mitogen-activated protein kinase-activated protein kinase 2 mediates apoptosis during lung vascular permeability by regulating movement of cleaved caspase 3.

Apoptosis is a key pathologic feature in acute lung injury. Animal studies have demonstrated that pathways regulating apoptosis are necessary in the development of acute lung injury, and that activation of p38 mitogen-activated protein kinase (MAPK) is linked to the initiation of the apoptotic cascade. In this study, we assessed the role of the MAPK-activated protein kinase (MK) 2, one of p38 MAPK's immediate downstream effectors, in the development of apoptosis in an animal model of LPS-induced pulmonary vascular permeability. Our results indicate that wild-type (WT) mice exposed to LPS demonstrate increased apoptosis, as evidenced by cleavage of caspase 3 and poly (ADP-ribose) polymerase 1 and increased deoxynucleotidyl transferase-mediated dUDP nick-end labeling staining, which is accompanied by increases in markers of vascular permeability. In contrast, MK2(-/-) mice are protected from pulmonary vascular permeability and apoptosis in response to LPS. Although there was no difference in activation of caspase 3 in MK2(-/-) compared with WT mice, interestingly, cleaved caspase 3 translocated to the nucleus in WT mice while it remained in the cytosol of MK2(-/-) mice in response to LPS. In separate experiments, LPS-induced apoptosis in human lung microvascular endothelial cells was also associated with nuclear translocation of cleaved caspase 3 and apoptosis, which were both prevented by MK2 silencing. In conclusion, our data suggest that MK2 plays a critical role in the development of apoptosis and pulmonary vascular permeability, and its effects on apoptosis are in part related to its ability to regulate nuclear translocation of cleaved caspase 3.

Extracorporeal membrane oxygenation as a bridge to lung transplantation: Practice patterns and patient outcomes.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is increasingly relied on to bridge patients with respiratory failure to lung transplantation despite limited evidence for its use in this setting. This study evaluated longitudinal trends in practice patterns, patient characteristics, and outcomes in patients bridged with ECMO to lung transplant. METHODS: A retrospective review of all adult isolated lung transplant patients in the United Network for Organ Sharing database between 2000 and 2019 was performed. Patients were classified as "ECMO" if supported with ECMO at the time of listing or transplantation and "non-ECMO" otherwise. Linear regression was used to evaluate trends in patient demographics during the study period. Trends in mortality were evaluated using Cox proportional hazards modeling, with time period as the primary covariate (2000-2004, 2005-2009, 2010-2014, or 2015-2019) and age, time on the waitlist, and underlying diagnosis as covariates. RESULTS: The number of patients included were 40,866, of whom 1,387 (3.4%) were classified as ECMO and 39,479 (96.6%) as no ECMO. Average age and initial Lung Allocation Score increased significantly during the study period in both cohorts, but occurred at a slower rate in the ECMO population. The hazard of death was significantly lower in more recent years (2015-2019) for both the ECMO and non-ECMO cohorts (aHR (adjusted hazards ratio) 0.59, 95% confidence interval (CI) 0.37-0.96 and aHR 0.74, 95% CI 0.70-0.79) when compared to the early years (2000-2004) of the study period. CONCLUSIONS: Post-transplantation survival for patients bridged to transplantation with ECMO demonstrates ongoing improvement despite cannulation of progressively older and sicker patients.

Hemorrhage and thrombosis in COVID-19-patients supported with extracorporeal membrane oxygenation: an international study based on the COVID-19 critical care consortium.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a rescue therapy in patients with severe acute respiratory distress syndrome (ARDS) secondary to COVID-19. While bleeding and thrombosis complicate ECMO, these events may also occur secondary to COVID-19. Data regarding bleeding and thrombotic events in COVID-19 patients on ECMO are sparse. METHODS: Using the COVID-19 Critical Care Consortium database, we conducted a retrospective analysis on adult patients with severe COVID-19 requiring ECMO, including centers globally from 01/2020 to 06/2022, to determine the risk of ICU mortality associated with the occurrence of bleeding and clotting disorders. RESULTS: Among 1,248 COVID-19 patients receiving ECMO support in the registry, coagulation complications were reported in 469 cases (38%), among whom 252 (54%) experienced hemorrhagic complications, 165 (35%) thrombotic complications, and 52 (11%) both. The hazard ratio (HR) for Intensive Care Unit mortality was higher in those with hemorrhagic-only complications than those with neither complication (adjusted HR = 1.60, 95% CI 1.28-1.99, p < 0.001). Death was reported in 617 of the 1248 (49.4%) with multiorgan failure (n = 257 of 617 [42%]), followed by respiratory failure (n = 130 of 617 [21%]) and septic shock [n = 55 of 617 (8.9%)] the leading causes. CONCLUSIONS: Coagulation disorders are frequent in COVID-19 ARDS patients receiving ECMO. Bleeding events contribute substantially to mortality in this cohort. However, this risk may be lower than previously reported in single-nation studies or early case reports. Trial registration ACTRN12620000421932 ( https://covid19.cochrane.org/studies/crs-13513201 ).

How to Do It: A Safe Bedside Protocol for Dual-Lumen Right Internal Jugular Cannulation for Venovenous Extracorporeal Membrane Oxygenation in COVID-19 Patients With Severe Acute Respiratory Distress Syndrome.

In appropriately selected patients with COVID-19 acute respiratory distress syndrome, venovenous extracorporeal membrane oxygenation (VV ECMO) may offer a promising bridge to lung recovery or lung transplantation if lung recovery fails. Although the cannulation technique for VV ECMO via a right internal jugular (RIJ) dual-lumen catheter (DLC) requires expertise and guidance by either fluoroscopy or transesophageal echocardiography (TEE), it offers theoretical circulatory support advantages by using bicaval venous drainage to deliver oxygenated blood systemically with minimal recirculation as compared with the femoral vein and RIJ dual-site cannula configuration. In addition, patients are often too unstable to transport safely to an operating room or catheterization laboratory, and fluoroscopy is not always readily available to guide RIJ DLC placement. Here, we provide a comprehensive description of a safe, bedside protocol for VV ECMO cannulation via a RIJ DLC under TEE guidance. We will report our center's experience (March 30, 2020 to November 21, 2021) and discuss important hemodynamic, safety, and infection control considerations.

Analgosedation in Critically Ill Adults Receiving Extracorporeal Membrane Oxygenation Support.

Extracorporeal membrane oxygenation (ECMO) is an increasingly utilized intervention for cardiopulmonary failure. Analgosedation during ECMO support is essential to ensure adequate pain and agitation control and ventilator synchrony, optimize ECMO support, facilitate patient assessment, and minimize adverse events. Although the principles of analgosedation are likely similar for all critically ill patients, ECMO circuitry alters medication pharmacodynamics and pharmacokinetics. The lack of clinical guidelines for analgosedation during ECMO, especially at times of medication shortage, can affect patient management. Here, we review pharmacological considerations, protocols, and special considerations for analgosedation in critically ill adults receiving ECMO support.

p53 mediates cigarette smoke-induced apoptosis of pulmonary endothelial cells: inhibitory effects of macrophage migration inhibitor factor.

Exposure to cigarette smoke (CS) is the most common cause of emphysema, a debilitating pulmonary disease histopathologically characterized by the irreversible destruction of lung architecture. Mounting evidence links enhanced endothelial apoptosis causally to the development of emphysema. However, the molecular determinants of human endothelial cell apoptosis and survival in response to CS are not fully defined. Such determinants could represent clinically relevant targets for intervention. We show here that CS extract (CSE) triggers the death of human pulmonary macrovascular endothelial cells (HPAECs) through a caspase 9-dependent apoptotic pathway. Exposure to CSE results in the increased expression of p53 in HPAECs. Using the p53 inhibitor, pifithrin-α (PFT-α), and RNA interference (RNAi) directed at p53, we demonstrate that p53 function and expression are required for CSE-mediated apoptosis. The expression of macrophage migration inhibitory factor (MIF), an antiapoptotic cytokine produced by HPAECs, also increases in response to CSE exposure. The addition of recombinant human MIF prevents cell death from exposure to CSE. Further, the suppression of MIF or its receptor/binding partner, Jun activation domain-binding protein 1 (Jab-1), with RNAi enhances the sensitivity of human pulmonary endothelial cells to CSE via a p53-dependent (PFT-α-inhibitable) pathway. Finally, we demonstrate that MIF is a negative regulator of p53 expression in response to CSE, placing MIF upstream of p53 as an antagonist of CSE-induced apoptosis. We conclude that MIF can protect human vascular endothelium from the toxic effects of CSE via the antagonism of p53-mediated apoptosis.

CD3+CD4-CD8- Double-negative αß T cells attenuate lung ischemia-reperfusion injury.

OBJECTIVE: Lung ischemia-reperfusion injury (IRI) is a common complication after lung transplantation, and immune cells have been implicated in modulating outcomes. We hypothesized that a newly described subset of αß T-cell receptor positive cells; that is, CD4-CD8- (double negative [DN]) T cells, are found in lungs and can protect against lung IRI. METHODS: Ischemia was induced in C57BL/6 mice by left pulmonary artery and vein occlusion for 30 minutes followed by 180 minutes of reperfusion. These mice were paired with sham hilar dissected surgical controls. In mice undergoing IRI, adoptive transfer of DN T cells or conventional T cells was performed 12 hours before occlusion. Flow cytometry was used to quantify T cells and inflammatory cytokines, and apoptotic signaling pathways were evaluated with immunoblotting. Lung injury was assessed with Evans blue dye extravasation. RESULTS: DN T cells were significantly higher (5.29% ± 1% vs 2.21% ± 3%; P < .01) in IRI lungs and secreted higher levels of interleukin-10 (30% ± 5% vs 6% ± 1%; P < .01) compared with surgical sham controls. Immunoblotting, hematoxylin and eosin staining and Evans blue dye demonstrated that adoptive transfer of DN T cells significantly decreased interstitial edema (P < .01) and attenuated apoptosis/cleaved caspase-3 expression in the lungs following lung IRI (P < .01). CONCLUSIONS: DN T cells traffic into lungs during IRI, and have tissue protective functions regulating inflammation and apoptosis. We propose a potential novel immunoregulatory function of DN T cells during lung IRI.

Traumatically Brain-Injured Donors and the Impact on Lung Transplantation Survival.

BACKGROUND: Concern has been raised over inferior lung transplantation survival associated with traumatic brain injury (TBI) organ donors. Our purpose was to explore the relationship between TBI donors and lung transplantation survival in the lung allocation score (LAS) era. METHODS: We queried the United Network for Organ Sharing Scientific Registry of Transplant Recipients and identified all adult (≥18 years) lung transplantations performed from May 4, 2005, to December 31, 2015. Recipients were dichotomized based on donor cause of death, TBI versus non-TBI, propensity score across eight variables (final LAS, intensive care unit admission before transplantation, extracorporeal membrane oxygenation before transplantation, donor age 50 years or older, cytomegalovirus antibody recipient-/donor+, ischemia time, annual center transplantation volume, single versus double lung transplantation), and matched 1:1 without replacement. Our primary outcomes were survival at 1, 3, and 5 years by Kaplan-Meier method. RESULTS: A total of 17,610 patients underwent isolated lung transplantation over the study period at 75 different transplantation centers. TBI was the leading cause of death in the donor population: 47% of all donors. Propensity score matching generated 6,782 well-matched donor TBI versus non-TBI pairs (all covariate p > 0.2). Risk-adjusted survival was similar between recipients of TBI donors versus non-TBI donors at 1 year (86% versus 86%, log-rank p = 0.27), 3 years (68% versus 68%, log-rank p = 0.47), and 5 years (55% versus 54%, log-rank p = 0.40). CONCLUSIONS: In the largest analysis of TBI donors and the impact on lung transplantation survival to date, we found similar survival out to 5 years in lung transplant recipients of TBI versus non-TBI donors, alleviating concerns over continued transplantation with this unique donor population.

Imatinib Is Protective Against Ischemia-Reperfusion Injury in an Ex Vivo Rabbit Model of Lung Injury.

BACKGROUND: Ischemia-reperfusion injury is characterized by an increase in oxidative stress and leads to significant morbidity and death. The tyrosine kinase c-Abl is activated by oxidative stress and mediates processes that affect endothelial barrier function. We hypothesized treatment with the c-Abl inhibitor imatinib would be protective against ischemia-reperfusion injury in our ex vivo rabbit model. METHODS: Heart-lung blocs were harvested from rabbits and stored in cold in Perfadex (Vitrolife, Englewood, CO) for 18 hours. Blocs were reperfused for 2 hours in an ex vivo circuit with donor rabbit blood alone (untreated group, n = 7) or donor rabbit blood and 4 mg imatinib (treatment group, n = 10). Serial clinical variables measured every 15 minutes (arterial oxygen and carbon dioxide tension and mean pulmonary artery pressures) and biochemistry of tissue samples before and after reperfusion were assessed. RESULTS: Compared with untreated lungs, imatinib treatment improved physiologic parameters, including oxygen, carbon dioxide, and pulmonary artery pressures. Imatinib-treated lungs had less vascular barrier dysfunction as quantified by wet-to-dry weight ratios and bronchoalveolar lavage protein concentrations. Treated lungs showed less inflammation as measured by bronchoalveolar lavage myeloperoxidase assay, less mitochondrial reactive oxygen species production, and increased antioxidant catalase levels. Finally, imatinib protected lungs from DNA damage and p53 upregulation. CONCLUSIONS: Imatinib treatment significantly improved the physiologic performance of reperfused lungs and biochemical indicators associated with reperfusion injury in this ex vivo model. Further study is necessary to elucidate the mechanism of tyrosine kinase inhibition in lungs exposed to ischemia and reperfusion.

XOR inhibition with febuxostat accelerates pulmonary endothelial barrier recovery and improves survival in lipopolysaccharide-induced murine sepsis.

Sepsis is a leading cause of death among patients in the intensive care unit, resulting from multi-organ failure. Activity of xanthine oxidoreductase (XOR), a reactive oxygen species (ROS) producing enzyme, is known to be elevated in nonsurvivors of sepsis compared to survivors. We have previously demonstrated that XOR is critical for ventilator-induced lung injury. Using febuxostat, a novel nonpurine inhibitor of XOR, we sought to determine the role of XOR inhibition in a murine model of sepsis-induced lung injury and mortality. C57BL/6J mice were subjected to intravenous (IV) lipopolysaccharide (LPS) for various time points, and lungs were harvested for analyses. Subsets of mice were treated with febuxostat, pre or post LPS exposure, or vehicle. Separate groups of mice were followed up for mortality after LPS exposure. After 24 hr of IV LPS, mice exhibited an increase in XOR activity in lung tissue and a significant increase in pulmonary endothelial barrier disruption. Pretreatment of animals with febuxostat before exposure to LPS, or treatment 4 h after LPS, resulted in complete abrogation of XOR activity. Inhibition of XOR with febuxostat did not prevent LPS-induced pulmonary vascular permeability at 24 h, however, it accelerated recovery of the pulmonary endothelial barrier integrity in response to LPS exposure. Furthermore, treatment with febuxostat resulted in significant reduction in mortality. Inhibition of XOR with febuxostat accelerates recovery of the pulmonary endothelial barrier and prevents LPS-induced mortality, whether given before or after exposure to LPS.

Tobacco Smoke Exposure Reduces Paraoxonase Activity in a Murine Model.

AIM: To demonstrate a direct inhibitory effect of cigarette smoke exposure on paraoxonase 1 activity in a murine in vivo model. METHODS: At 8 weeks old, we randomized 10 C57/bl6 mice to an environment consisting of either filtered air or cigarette smoke for 6 months. Smoke exposure (7 hours per day, 5 days per week) was standardized using a model TE-10 smoking machine and adjusted to maintain constant sidestream and mainstream smoke. After 6 months of exposure, we assessed differences in lung air space, cholesterol, lipid, and lipoprotein profiles, as well as paraoxonase activity in mice exposed to cigarette smoke extract compared to unexposed control mice. RESULTS: Cigarette smoke exposure by the protocol used was sufficient to result in pathologic changes in lung architecture consistent with emphysema. Specifically, we observed that mice exposed to cigarette smoke had a significantly higher mean linear chord length compared to animals that were exposed to filtered air (p<0.02). Despite this exposure, no differences in total HDL-cholesterol levels or HDL-cholesterol sub-fractions (i.e. HDL2 and HDL3 fractions) were noted between smoke-exposed and unexposed animals (p=1.00, 0.6, and 0.4, respectively). Notably, mean HDL-cholesterol levels were identical between groups (92.8 vs 92.8 mg/dL, p=1.0). Paraoxonase activity, however, was markedly reduced in mice exposed to cigarette smoke compared to those who were not exposed (102, SD=9.6 vs 144, SD=4.1 units of activity, respectively, p=0.002). CONCLUSION: In this murine model, tobacco smoke exposure directly inhibits paraoxonase activity independently of HDL-cholesterol levels rather than indirectly via reduction in HDL-cholesterol levels.

Impaired Renal Function Should Not Be a Barrier to Transplantation in Patients With Cystic Fibrosis.

BACKGROUND: Previous studies have demonstrated an association between pretransplantation renal dysfunction (PRD) and increased mortality after lung transplantation (LT). The purpose of this study was to determine whether PRD impacts survival after LT in patients with cystic fibrosis (CF). METHODS: We queried the United Network for Organ Sharing (UNOS) database to identify all adult (≥18 years) recipients with CF who underwent isolated LT from May 4, 2005 to December 31, 2014. We separated recipients into those with and those without PRD (glomerular filtration rate [GFR] ≤60 mL/min). We excluded patients who required dialysis before transplantation. Kaplan-Meier analysis was used to assess unadjusted survival differences. Cox proportional hazards modeling was then performed across 26 variables to assess the risk-adjusted impact of PRD on 1-, 3-, and 5-year mortality. RESULTS: Isolated LT was performed on 1,830 patients with CF; 17 patients were excluded because of pretransplantation dialysis. Eighty-two of 1,813 patients (4.5%) had PRD (GFR ≤60 mL/min). Kaplan-Meier analysis revealed no survival differences between PRD and non-PRD groups at 1 year (85.3% versus 89.5%; log-rank p = 0.23), 3 years (71.0% versus 72.5%; p = 0.57), or 5 years (63.3% versus 59.8%; p = 0.95). After risk adjustment, PRD was not independently associated with an increased hazard for mortality at 1 year (hazard ratio [HR], 1.38 [95% confidence interval [CI], 0.74-2.58]; p = 0.31), 3 years (HR, 1.44 [95% CI, 0.92-2.24]; p = 0.11), or 5 years (HR, 1.30 [95% CI, 0.86-1.94]; p = 0.29). CONCLUSIONS: Although PRD has historically served as a relative contraindication to LT, our study is the first to suggest that among CF recipients, PRD was not associated with increased hazard for mortality out to 5 years after LT.

Lung Transplant Mortality Is Improving in Recipients With a Lung Allocation Score in the Upper Quartile.

BACKGROUND: Since the introduction of the Lung Allocation Score (LAS), the mean LAS has risen. Still, it remains uncertain whether mortality has improved in the most severely ill lung transplant recipients over this time period. METHODS: Using the United Network for Organ Sharing database, we identified 3,548 adult lung transplant recipients from May 4, 2005, to March 31, 2014, with a match-time LAS in the upper quartile (>75th%ile). We divided this population across three eras: 1 = May 4, 2005, to December 31, 2008 (n = 1,280); 2 = January 1, 2009, to December 31, 2011 (n = 1,266); and 3 = January 1, 2012, to March 31, 2014 (n = 1,002). Cox proportional hazards models were constructed for the primary outcomes of 30-day and 1-year mortality to assess the independent impact of the era of transplantation. RESULTS: The mean LAS at time of transplant for patients in the upper quartile in eras 1, 2, and 3 was 63, 73, and 79, respectively (p < 0.001). Later eras of transplantation benefited from a significant improvement in survival at 1 year (log-rank p = 0.001) but not at 30 days (log-rank p = 0.152). After risk adjustment, lung transplantation in more recent eras was associated with improved mortality at both 30 days (era 3 hazard ratio [HR] = 0.50, 95% confidence interval [CI] 0.32% to 0.78%, p = 0.002) and 1 year (era 2 HR = 0.77, 95% CI 0.64% to 0.94%, p = 0.008; era 3 HR = 0.54, 95% CI 0.43% to 0.68%, p < 0.001). CONCLUSIONS: Despite a progressively rising LAS, survival is improving among recipients with the highest LAS at the time of lung transplantation. This calls into question the notion of a maximum LAS beyond which lung transplantation becomes futile, a so-called LAS ceiling.