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1.  Alcohol and Lung Injury and Immunity 
Annually, excessive alcohol use accounts for more than $220 billion in economic costs and 80,000 deaths, making excessive alcohol use the third leading lifestyle-related cause of death in the US. Patients with an alcohol-use disorder (AUD) also have an increased susceptibility to respiratory pathogens and lung injury, including a 2–4-fold increased risk of acute respiratory distress syndrome (ARDS). This review investigates some of the potential mechanisms by which alcohol causes lung injury and impairs lung immunity. In intoxicated individuals with burn injuries, activation of the gut-liver axis drives pulmonary inflammation, thereby negatively impacting morbidity and mortality. In the lung, the upper airway is the first checkpoint to fail in microbe clearance during alcohol-induced lung immune dysfunction. Brief and prolonged alcohol exposure drive different post-translational modifications of novel proteins that control cilia function. Proteomic approaches are needed to identify novel alcohol targets and post-translational modifications in airway cilia that are involved in alcohol-dependent signal transduction pathways. When the upper airway fails to clear inhaled pathogens, they enter the alveolar space where they are primarily cleared by alveolar macrophages (AM). With chronic alcohol ingestion, oxidative stress pathways in the AMs are stimulated, thereby impairing AM immune capacity and pathogen clearance. The epidemiology of pneumococcal pneumonia and AUDs is well established, as both increased predisposition and illness severity have been reported. AUD subjects have increased susceptibility to pneumococcal pneumonia infections, which may be due to the pro-inflammatory response of AMs, leading to increased oxidative stress.
doi:10.1016/j.alcohol.2016.08.005
PMCID: PMC5319482  PMID: 27788778
alcohol; lung immunity; lung injury; gut-liver-lung axis; airway cilia; alveolar macrophage
2.  Proceedings of the 14th annual conference of INEBRIA 
Holloway, Aisha S. | Ferguson, Jennifer | Landale, Sarah | Cariola, Laura | Newbury-Birch, Dorothy | Flynn, Amy | Knight, John R. | Sherritt, Lon | Harris, Sion K. | O’Donnell, Amy J. | Kaner, Eileen | Hanratty, Barbara | Loree, Amy M. | Yonkers, Kimberly A. | Ondersma, Steven J. | Gilstead-Hayden, Kate | Martino, Steve | Adam, Angeline | Schwartz, Robert P. | Wu, Li-Tzy | Subramaniam, Geetha | Sharma, Gaurav | McNeely, Jennifer | Berman, Anne H. | Kolaas, Karoline | Petersén, Elisabeth | Bendtsen, Preben | Hedman, Erik | Linderoth, Catharina | Müssener, Ulrika | Sinadinovic, Kristina | Spak, Fredrik | Gremyr, Ida | Thurang, Anna | Mitchell, Ann M. | Finnell, Deborah | Savage, Christine L. | Mahmoud, Khadejah F. | Riordan, Benjamin C. | Conner, Tamlin S. | Flett, Jayde A. M. | Scarf, Damian | McRee, Bonnie | Vendetti, Janice | Gallucci, Karen Steinberg | Robaina, Kate | Clark, Brendan J. | Jones, Jacqueline | Reed, Kathryne D. | Hodapp, Rachel M. | Douglas, Ivor | Burnham, Ellen L. | Aagaard, Laura | Cook, Paul F. | Harris, Brett R. | Yu, Jiang | Wolff, Margaret | Rogers, Meighan | Barbosa, Carolina | Wedehase, Brendan J. | Dunlap, Laura J. | Mitchell, Shannon G. | Dusek, Kristi A. | Gryczynski, Jan | Kirk, Arethusa S. | Oros, Marla T. | Hosler, Colleen | O’Grady, Kevin E. | Brown, Barry S. | Angus, Colin | Sherborne, Sidney | Gillespie, Duncan | Meier, Petra | Brennan, Alan | de Vargas, Divane | Soares, Janaina | Castelblanco, Donna | Doran, Kelly M. | Wittman, Ian | Shelley, Donna | Rotrosen, John | Gelberg, Lillian | Edelman, E. Jennifer | Maisto, Stephen A. | Hansen, Nathan B. | Cutter, Christopher J. | Deng, Yanhong | Dziura, James | Fiellin, Lynn E. | O’Connor, Patrick G. | Bedimo, Roger | Gibert, Cynthia | Marconi, Vincent C. | Rimland, David | Rodriguez-Barradas, Maria C. | Simberkoff, Michael S. | Justice, Amy C. | Bryant, Kendall J. | Fiellin, David A. | Giles, Emma L. | Coulton, Simon | Deluca, Paolo | Drummond, Colin | Howel, Denise | McColl, Elaine | McGovern, Ruth | Scott, Stephanie | Stamp, Elaine | Sumnall, Harry | Vale, Luke | Alabani, Viviana | Atkinson, Amanda | Boniface, Sadie | Frankham, Jo | Gilvarry, Eilish | Hendrie, Nadine | Howe, Nicola | McGeechan, Grant J. | Ramsey, Amy | Stanley, Grant | Clephane, Justine | Gardiner, David | Holmes, John | Martin, Neil | Shevills, Colin | Soutar, Melanie | Chi, Felicia W. | Weisner, Constance | Ross, Thekla B. | Mertens, Jennifer | Sterling, Stacy A. | Shorter, Gillian W. | Heather, Nick | Bray, Jeremy | Cohen, Hildie A. | McPherson, Tracy L. | Adam, Cyrille | López-Pelayo, Hugo | Gual, Antoni | Segura-Garcia, Lidia | Colom, Joan | Ornelas, India J. | Doyle, Suzanne | Donovan, Dennis | Duran, Bonnie | Torres, Vanessa | Gaume, Jacques | Grazioli, Véronique | Fortini, Cristiana | Paroz, Sophie | Bertholet, Nicolas | Daeppen, Jean-Bernard | Satterfield, Jason M. | Gregorich, Steven | Alvarado, Nicholas J. | Muñoz, Ricardo | Kulieva, Gozel | Vijayaraghavan, Maya | Adam, Angéline | Cunningham, John A. | Díaz, Estela | Palacio-Vieira, Jorge | Godinho, Alexandra | Kushir, Vladyslav | O’Brien, Kimberly H. M. | Aguinaldo, Laika D. | Sellers, Christina M. | Spirito, Anthony | Chang, Grace | Blake-Lamb, Tiffany | LaFave, Lea R. Ayers | Thies, Kathleen M. | Pepin, Amy L. | Sprangers, Kara E. | Bradley, Martha | Jorgensen, Shasta | Catano, Nico A. | Murray, Adelaide R. | Schachter, Deborah | Andersen, Ronald M. | Rey, Guillermina Natera | Vahidi, Mani | Rico, Melvin W. | Baumeister, Sebastian E. | Johansson, Magnus | Sinadinovic, Christina | Hermansson, Ulric | Andreasson, Sven | O’Grady, Megan A. | Kapoor, Sandeep | Akkari, Cherine | Bernal, Camila | Pappacena, Kristen | Morley, Jeanne | Auerbach, Mark | Neighbors, Charles J. | Kwon, Nancy | Conigliaro, Joseph | Morgenstern, Jon | Magill, Molly | Apodaca, Timothy R. | Borsari, Brian | Hoadley, Ariel | Scott Tonigan, J. | Moyers, Theresa | Fitzgerald, Niamh M. | Schölin, Lisa | Barticevic, Nicolas | Zuzulich, Soledad | Poblete, Fernando | Norambuena, Pablo | Sacco, Paul | Ting, Laura | Beaulieu, Michele | Wallace, Paul George | Andrews, Matthew | Daley, Kate | Shenker, Don | Gallagher, Louise | Watson, Rod | Weaver, Tim | Bruguera, Pol | Oliveras, Clara | Gavotti, Carolina | Barrio, Pablo | Braddick, Fleur | Miquel, Laia | Suárez, Montse | Bruguera, Carla | Brown, Richard L. | Capell, Julie Whelan | Paul Moberg, D. | Maslowsky, Julie | Saunders, Laura A. | McCormack, Ryan P. | Scheidell, Joy | Gonzalez, Mirelis | Bauroth, Sabrina | Liu, Weiwei | Lindsay, Dawn L. | Lincoln, Piper | Hagle, Holly | Wallhed Finn, Sara | Hammarberg, Anders | Andréasson, Sven | King, Sarah E. | Vargo, Rachael | Kameg, Brayden N. | Acquavita, Shauna P. | Van Loon, Ruth Anne | Smith, Rachel | Brehm, Bonnie J. | Diers, Tiffiny | Kim, Karissa | Barker, Andrea | Jones, Ashley L. | Skinner, Asheley C. | Hinman, Agatha | Svikis, Dace S. | Thacker, Casey L. | Resnicow, Ken | Beatty, Jessica R. | Janisse, James | Puder, Karoline | Bakshi, Ann-Sofie | Milward, Joanna M. | Kimergard, Andreas | Garnett, Claire V. | Crane, David | Brown, Jamie | West, Robert | Michie, Susan | Rosendahl, Ingvar | Andersson, Claes | Gajecki, Mikael | Blankers, Matthijs | Donoghue, Kim | Lynch, Ellen | Maconochie, Ian | Phillips, Ceri | Pockett, Rhys | Phillips, Tom | Patton, R. | Russell, Ian | Strang, John | Stewart, Maureen T. | Quinn, Amity E. | Brolin, Mary | Evans, Brooke | Horgan, Constance M. | Liu, Junqing | McCree, Fern | Kanovsky, Doug | Oberlander, Tyler | Zhang, Huan | Hamlin, Ben | Saunders, Robert | Barton, Mary B. | Scholle, Sarah H. | Santora, Patricia | Bhatt, Chirag | Ahmed, Kazi | Hodgkin, Dominic | Gao, Wenwu | Merrick, Elizabeth L. | Drebing, Charles E. | Larson, Mary Jo | Sharma, Monica | Petry, Nancy M. | Saitz, Richard | Weisner, Constance M. | Young-Wolff, Kelly C. | Lu, Wendy Y. | Blosnich, John R. | Lehavot, Keren | Glass, Joseph E. | Williams, Emily C. | Bensley, Kara M. | Chan, Gary | Dombrowski, Julie | Fortney, John | Rubinsky, Anna D. | Lapham, Gwen T. | Forray, Ariadna | Olmstead, Todd A. | Gilstad-Hayden, Kathryn | Kershaw, Trace | Dillon, Pamela | Weaver, Michael F. | Grekin, Emily R. | Ellis, Jennifer D. | McGoron, Lucy | McGoron, Lucy
doi:10.1186/s13722-017-0087-8
PMCID: PMC5606215
3.  Azithromycin Use and Outcomes in Severe Sepsis Patients with and without Pneumonia 
Journal of critical care  2015;32:120-125.
Purpose
Studies investigating the association between macrolides and outcomes in both pulmonary and non-pulmonary critically-ill patients are limited. We aimed to examine the association between azithromycin use and clinical outcomes in severe sepsis patients with and without pneumonia receiving mechanical ventilation.
Materials and Methods
Retrospective cohort of 105 patients admitted to an adult intensive care unit (ICU) with severe sepsis in an urban university hospital. Multivariable linear regression was performed to assess the relationship between azithromycin use and the following outcomes: 28-day ICU-free days and 28-day ventilator free days.
Results
In univariate analysis, patients receiving azithromycin had nearly six more ICU-free days on average than patients not receiving azithromycin (p=0.005). The increased ICU-free days remained in multivariable analysis adjusting for age, sex, race, ICU type, and presence of shock (p=0.005). In stratified analysis examining the association of azithromycin use in severe sepsis patients without pneumonia (N=74), the results were similar to the full cohort.
Conclusion
Azithromycin was associated with more ICU-free days in severe sepsis patients with and without pneumonia. Further investigations are warranted to better elicit the association of macrolide use on clinical outcomes in severe sepsis patients, especially those without pneumonia.
doi:10.1016/j.jcrc.2015.12.010
PMCID: PMC4769933  PMID: 26803186
Macrolide; Severe Sepsis; Inflammation; Intensive Care Unit; Azithromycin; Mechanical Ventilation
4.  Alveolar macrophage inflammatory mediator expression is elevated in the setting of alcohol use disorders 
Alcohol use disorders (AUDs) are associated with increased susceptibility to pulmonary diseases, including bacterial pneumonia and acute respiratory distress syndrome (ARDS). Alveolar macrophages (AMs) play a vital role in the clearance of pathogens and regulation of inflammation, but these functions may be impaired in the setting of alcohol exposure. We examined the effect of AUDs on profiles of cytokines, chemokines, and growth factors in human AMs isolated from bronchoalveolar lavage (BAL) samples from 19 AUD subjects and 20 age, sex, and smoking-matched control subjects. By multiplex bead array, the lysates of AMs from subjects with AUDs had significant elevation in the cytokine tumor necrosis factor α (TNF-α), as well as chemokine (C-X-C motif) ligand 8 (CXCL8), CXCL10, and chemokine (C-C motif) ligand 5 (CCL5) (p<0.05). Additionally, a 1.8-fold increase in IL-1β, 2.0-fold increase in IL-6, 2.3-fold increase in interferon gamma (IFN-γ), 1.4-fold increase in CCL3, and a 2.3-fold increase in CCL4 was observed in the AUD group as compared to the control group. We also observed compensatory increases in the anti-inflammatory cytokine IL-1RA (p<0.05). AUD subjects had 5-fold higher levels of CXCL11 mRNA expression (p<0.05) and a 2.4-fold increase in IL-6 mRNA expression by RT-PCR as well. In these investigations, alcohol use disorders were associated with functional changes in human AMs, suggesting that chronic alcohol exposure portends a chronically pro-inflammatory profile in these cells.
doi:10.1016/j.alcohol.2015.11.003
PMCID: PMC4753084  PMID: 26781212
AUD; pulmonary; inflammation; alveolar macrophage; cytokine
5.  Extremes of Interferon-Stimulated Gene Expression Associate with Worse Outcomes in the Acute Respiratory Distress Syndrome 
PLoS ONE  2016;11(9):e0162490.
Acute Respiratory Distress Syndrome (ARDS) severity may be influenced by heterogeneity of neutrophil activation. Interferon-stimulated genes (ISG) are a broad gene family induced by Type I interferons, often as a response to viral infections, which evokes extensive immunomodulation. We tested the hypothesis that over- or under-expression of immunomodulatory ISG by neutrophils is associated with worse clinical outcomes in patients with ARDS. Genome-wide transcriptional profiles of circulating neutrophils isolated from patients with sepsis-induced ARDS (n = 31) and healthy controls (n = 19) were used to characterize ISG expression. Hierarchical clustering of expression identified 3 distinct subject groups with Low, Mid and High ISG expression. ISG accounting for the greatest variability in expression were identified (MX1, IFIT1, and ISG15) and used to analyze a prospective cohort at the Colorado ARDS Network site. One hundred twenty ARDS patients from four urban hospitals were enrolled within 72 hours of initiation of mechanical ventilation. Circulating neutrophils were isolated from patients and expression of ISG determined by PCR. Samples were stratified by standard deviation from the mean into High (n = 21), Mid, (n = 82) or Low (n = 17) ISG expression. Clinical outcomes were compared between patients with High or Low ISG expression to those with Mid-range expression. At enrollment, there were no differences in age, gender, co-existing medical conditions, or type of physiologic injury between cohorts. After adjusting for age, race, gender and BMI, patients with either High or Low ISG expression had significantly worse clinical outcomes than those in the Mid for number of 28-day ventilator- and ICU-free days (P = 0.0006 and 0.0004), as well as 90-day mortality and 90-day home with unassisted breathing (P = 0.02 and 0.004). These findings suggest extremes of ISG expression by circulating neutrophils from ARDS patients recovered early in the syndrome are associated with poorer clinical outcomes.
doi:10.1371/journal.pone.0162490
PMCID: PMC5015849  PMID: 27606687
6.  Chest Computed Tomography Features are Associated with Poorer Quality of Life in Acute Lung Injury Survivors 
Critical care medicine  2013;41(2):445-456.
Objectives
Despite decreasing mortality rates in acute lung injury (ALI), studies of long term physical function in ALI survivors have consistently reported poorer quality of life persisting years into recovery for reasons that are not completely understood. We sought to determine if pulmonary dysfunction is independently associated with functional impairment among ALI survivors, and to determine if high resolution computed tomography could be used to predict its development.
Design
Secondary analysis of data from a randomized controlled trial in ALI.
Setting
Intensive care units at three academic medical centers.
Patients
Patients diagnosed with ALI who had high resolution computed tomography scans performed at 14 and/or 180 days after diagnosis.
Interventions
None.
Measurements and main results
An objective radiologic scoring system was used to quantify patterns present on chest high resolution computed tomography obtained at 14 and 180 days in patients with ALI. These scores were correlated in univariable and multivariable analyses with pulmonary function testing and quality of life survey data obtained at 180 days. Eighty-nine patients had evaluable data at day 14, and 47 at 180 days. At 180 days, increased radiologic scores for reticulation were associated with a decreased total lung capacity, forced vital capacity, and diffusing capacity for carbon monoxide (p values all <0.002). Decrements in quality of life attributable to pulmonary dysfunction were most strongly associated with higher radiologic scores. Additionally, radiologic scores at 14 days independently predicted poorer quality of life at 180 days, accounting for age, severity of illness, pneumonia as the ALI risk factor, and length of time on mechanical ventilation.
Conclusions
Among survivors of ALI, increasing chest high resolution computed tomography involvement correlated with restrictive physiology and poorer health related quality of life, implicating pulmonary dysfunction as a potential contributor to activity limitation in these patients.
doi:10.1097/CCM.0b013e31826a5062
PMCID: PMC3671861  PMID: 23263616
reticulation; biomarker; restriction; fibroproliferation; radiologic; pulmonary function
7.  Mentoring K scholars: Strategies to support research mentors 
The goal of this paper is to present strategies utilized to support K scholar research mentors. K scholars are generally assistant professors who are close to developing independent research programs. Of all the various types of mentees, K scholars offer the greatest challenges, as well as the greatest rewards, for research mentors. To see one's mentee achieve independent PI status and become an established investigator is one of the great joys of being a research mentor. Research mentors for K scholars, however, may not directly benefit from their mentoring relationship, neither in terms of obtaining data to support their research program or laboratory, nor in assistance with grants or scientific papers. There is a pressing need for the research community to address the workload, institutional expectations and reward system for research mentors. The dearth of research mentors and role models in clinical translational science parallels the decreasing number of physicians choosing careers in clinical research. While there is limited empirical information on the effectiveness of mentor support mechanisms, this white paper concludes that providing mentor support is critical to expanding the available pool of mentors, as well as providing training opportunities for K scholars.
doi:10.1111/j.1752-8062.2011.00286.x
PMCID: PMC3136377  PMID: 21707951
translational research; salary; protected time; resources
8.  Selection of Research Mentors for K Funded Scholars 
Mentoring is an important element in the training of new investigators, particularly for KL2, K12, K08, and K23 funded scholars who are often physicians or other clinicians with limited prior research experience. Matching K scholars with appropriate mentors who have the mentoring skills and available time is an ongoing challenge for most universities. The goal of this paper is to present a variety of strategies used to select mentors for K awardees. The information presented in this special communication is derived from the literature, a national survey of CTSA leaders, as well as K scholar and K mentor focus groups.
Some of the mentor selection methods discussed in this paper include a) having the scholar find a mentor as part of the application process for the award, b) selecting mentors post award, c) expecting the chair of the department to identify a mentor(s), d) using a committee to match the scholar and a mentor based on a pool of approved mentors e) selecting additional mentors as the scholar’s research program develops. The paper concludes that mentor selection requires an ongoing programmatic approach with the active participation of K scholars, CTSA program leaders, center directors, research deans and chairs.
doi:10.1111/j.1752-8062.2011.00273.x
PMCID: PMC3072229  PMID: 21463493
research mentor selection
9.  Alveolar Macrophage Gene Expression is altered in the Setting of Alcohol Use Disorders 
Background
Alcohol use disorders (AUDs) are associated with an increased susceptibility to a variety of common and devastating pulmonary diseases including community- and hospital-acquired pneumonias, as well as the acute respiratory distress syndrome (ARDS). Alveolar macrophages play an important role in preventing the development of these disorders through maintaining lung sterility and resolving lung inflammation. Although alcohol exposure has been associated with aberrant alveolar macrophage function in animal models, the clinical relevance of these observations in humans is not established. Therefore, we sought to determine the effects of AUDs on human alveolar macrophage gene expression.
Methods
Whole genome microarray analysis was performed on alveolar macrophages obtained by bronchoalveolar lavage from a test cohort of subjects with AUDs (n=7), and controls (n=7) who were pair-matched on age, gender, and smoking. Probe set expression differences in this cohort were validated by real time reverse transcription-polymerase chain reaction (RT RT-PCR). Functional analysis with web-based bioinformatics tools was utilized with microarray data to assess differentially expressed candidate genes (p<0.01) based on alcohol consumption. Alveolar macrophage mRNA samples from a second cohort of subjects with AUDs (n=7) and controls (n=7) were used to confirm gene expression differences related to AUDs. Results: In both the test and confirmatory cohorts, AUDs were associated with upregulation of alveolar macrophage gene expression related to apoptosis, including perforin-1, granzyme A, and CXCR4 (fusin). Pathways governing the regulation of progression through cell cycle and immune response were also affected, as was upregulation of gene expression for mitochondrial superoxide dismutase. Overall, 12 genes’ expression was affected by AUDs independent of smoking.
Conclusions
AUDs are associated with unique changes in human alveolar macrophage gene expression. Novel therapies targeting alveolar macrophage gene expression in the setting of AUDs may prove to be clinically useful in limiting susceptibility for pulmonary disorders in these individuals.
doi:10.1111/j.1530-0277.2010.01344.x
PMCID: PMC3059108  PMID: 21121937
pneumonia; acute lung injury; apoptosis; perforin; human
10.  Acute Lung Injury but Not Sepsis Is Associated with Increased Colony Formation by Peripheral Blood Mononuclear Cells 
Acute lung injury (ALI) and severe sepsis are common critical illnesses associated with the mobilization of bone marrow–derived cells into the circulation. By identifying and determining these cells' functional characteristics, unique prognostic biomarkers can be developed to help investigators understand the mechanisms underlying the pathophysiology of these disorders. We previously demonstrated an increased colony-forming unit (CFU) ability of circulating peripheral blood mononuclear cells (PBMCs) in patients with ALI, compared with healthy control subjects, that also correlated with improved survival. Here we hypothesized that the increased CFUs in ALI are associated with lung injury, and therefore ALI will result in an increased number of CFUs compared with patients exhibiting severe sepsis. To test this, blood was collected from 80 patients (63 with ALI, and 17 with severe sepsis) within 72 hours of diagnosis, and from 5 healthy control subjects. A CFU assay was performed on isolated PBMCs. Lung injury scores and the need for mechanical ventilation were greater in patients with ALI than in patients with severe sepsis (P < 0.0001 for each). CFU numbers were highest in patients with ALI compared with patients manifesting severe sepsis or control subjects (median CFU number [25–75% quartiles] of 61 [13–104] versus 17 [3–34] versus 5 [2–13], P < 0.0005). A trend toward improved survival was demonstrated in patients with high (≥ 48) CFUs (P = 0.06). No relationship between CFUs and mechanical ventilation was evident. Our findings suggest that increased colony-forming ability by PBMCs in ALI results from lung injury, independent of sepsis and mechanical ventilation. Factors contributing to colony formation by PBMCs in ALI, and the role PBMCs play in its pathogenesis remain to be fully established.
doi:10.1165/rcmb.2009-0015OC
PMCID: PMC2933548  PMID: 19843706
endothelium; critical illness; repair; prognosis; ARDS
11.  Mentoring K Scholars: Strategies to Support Research Mentors 
Abstract
The goal of this paper is to present strategies utilized to support K scholar research mentors. K scholars are generally assistant professors who are close to developing independent research programs. Of all the various types of mentees, K scholars offer the greatest challenges, as well as the greatest rewards, for research mentors. To see one’s mentee achieve independent PI status and become an established investigator is one of the great joys of being a research mentor. Research mentors for K scholars, however, may not directly benefit from their mentoring relationship, neither in terms of obtaining data to support their research program or laboratory, nor in assistance with grants or scientific papers. There is a pressing need for the research community to address the workload, institutional expectations, and reward system for research mentors. The dearth of research mentors and role models in clinical translational science parallels the decreasing number of physicians choosing careers in clinical research. While there is limited empirical information on the effectiveness of mentor support mechanisms, this white paper concludes that providing mentor support is critical to expanding the available pool of mentors, as well as providing training opportunities for K scholars. Clin Trans Sci 2011; Volume 4: 199–203
doi:10.1111/j.1752-8062.2011.00286.x
PMCID: PMC3136377  PMID: 21707951
translational research; salary; protected time; resources
12.  Selection of Research Mentors for K‐Funded Scholars 
doi:10.1111/j.1752-8062.2011.00273.x
PMCID: PMC3072229  PMID: 21463493
14.  Metabolic Consequences of Chronic Alcohol Abuse in Non-Smokers: A Pilot Study 
PLoS ONE  2015;10(6):e0129570.
An alcohol use disorder (AUD) is associated with an increased susceptibility to respiratory infection and injury and, upon hospitalization, higher mortality rates. Studies in model systems show effects of alcohol on mitochondrial function, lipid metabolism and antioxidant systems. The present study applied high-resolution metabolomics to test for these changes in bronchoalveolar lavage fluid (BALF) of subjects with an AUD. Smokers were excluded to avoid confounding effects and compliance was verified by cotinine measurements. Statistically significant metabolic features, differentially expressed by control and AUD subjects, were identified by statistical and bioinformatic methods. The results show that fatty acid and acylcarnitine concentrations were increased in AUD subjects, consistent with perturbed mitochondrial and lipid metabolism. Decreased concentrations of methyl-donor compounds suggest altered one-carbon metabolism and oxidative stress. An accumulation of peptides suggests proteolytic activity, which could reflect altered epithelial barrier function. Two metabolites of possible microbial origin suggest subclinical bacterial infection. Furthermore, increased diacetylspermine suggests additional metabolic perturbations, which could contribute to dysregulated alveolar macrophage function and vulnerability to infection. Together, the results show an extended metabolic consequence of AUD in the bronchoalveolar space.
doi:10.1371/journal.pone.0129570
PMCID: PMC4477879  PMID: 26102199
15.  Neuroendocrine Signaling Via the Serotonin Transporter Regulates Clearance of Apoptotic Cells* 
The Journal of Biological Chemistry  2014;289(15):10466-10475.
Background: Serotonin (5-HT) contributes to the pathogenesis of chronic inflammatory diseases known to have defects in apoptotic cell removal (i.e. efferocytosis).
Results: 5-HT impairs macrophage efferocytosis via 5-HT transporter-dependent activation of the RhoA/Rho kinase pathway.
Conclusion: Results show a novel mechanism by which 5-HT might disrupt resolution of inflammation.
Significance: Targeting the 5-HT transporter may have a therapeutic role in chronic inflammatory disorders.
Serotonin (5-hydroxytryptamine; 5-HT) is a CNS neurotransmitter increasingly recognized to exert immunomodulatory effects outside the CNS that contribute to the pathogenesis of autoimmune and chronic inflammatory diseases. 5-HT signals to activate the RhoA/Rho kinase (ROCK) pathway, a pathway known for its ability to regulate phagocytosis. The clearance of apoptotic cells (i.e. efferocytosis) is a key modulator of the immune response that is inhibited by the RhoA/ROCK pathway. Because efferocytosis is defective in many of the same illnesses where 5-HT has been implicated in disease pathogenesis, we hypothesized that 5-HT would suppress efferocytosis via activation of RhoA/ROCK. The effect of 5-HT on efferocytosis was examined in murine peritoneal and human alveolar macrophages, and its mechanisms were investigated using pharmacologic blockade and genetic deletion. 5-HT impaired efferocytosis by murine peritoneal macrophages and human alveolar macrophages. 5-HT increased phosphorylation of myosin phosphatase subunit 1 (Mypt-1), a known ROCK target, and inhibitors of RhoA and ROCK reversed the suppressive effect of 5-HT on efferocytosis. Peritoneal macrophages expressed the 5-HT transporter and 5-HT receptors (R) 2a, 2b, but not 2c. Inhibition of 5-HTR2a and 5-HTR2b had no effect on efferocytosis, but blockade of the 5-HT transporter prevented 5-HT-impaired efferocytosis. Genetic deletion of the 5-HT transporter inhibited 5-HT uptake into peritoneal macrophages, prevented 5-HT-induced phosphorylation of Mypt-1, reversed the inhibitory effect of 5-HT on efferocytosis, and decreased cellular peritoneal inflammation. These results suggest a novel mechanism by which 5-HT might disrupt efferocytosis and contribute to the pathogenesis of autoimmune and chronic inflammatory diseases.
doi:10.1074/jbc.M113.482299
PMCID: PMC4036168  PMID: 24570000
Autoimmune Diseases; Inflammation; Lung; Phagocytosis; RhoA; Efferocytosis; Rho Kinase; Serotonin Receptors
17.  Healthcare Utilization in Medical Intensive Care Unit Survivors with Alcohol Withdrawal 
Background
Rehospitalization is an important and costly outcome that occurs commonly in several diseases encountered in the medical intensive care unit (ICU). Although alcohol use disorders are present in 40% of ICU survivors and alcohol withdrawal is the most common alcohol-related reason for admission to an ICU, rates and predictors of rehospitalization have not been previously reported in this population.
Methods
We conducted a retrospective cohort study of medical ICU survivors with a primary or secondary discharge diagnosis of alcohol withdrawal using two administrative databases. The primary outcome was time to rehospitalization or death. Secondary outcomes included time to first emergency department or urgent care clinic visit in the subset of ICU survivors who were not rehospitalized. Cox proportional hazard models were adjusted for age, gender, race, homelessness, smoking, and payer source.
Results
Of 1,178 patients discharged from the medical ICU over the study period, 468 (40%) were readmitted to the hospital and 54 (4%) died within 1 year. Schizophrenia (HR 2.23, 95% CI 1.57, 3.34, p < 0.001), anxiety disorder (HR 2.04, 95% CI 1.30, 3.32, p < 0.01), depression (HR 1.62, 95% CI 1.05, 2.40, p = 0.03), and Deyo comorbidity score ≥ 3 (HR 1.43, 95% CI 1.09, 1.1.89, p = 0.01) were significant predictors of time to death or first rehospitalization. Bipolar disorder was associated with time to first emergency department or urgent care clinic visit (HR 2.03, 95% CI 1.24, 3.62, p < 0.01) in the 656 patients who were alive and not rehospitalized within one year.
Conclusion
The presence of a psychiatric comorbidity is a significant predictor of multiple measures of unplanned healthcare utilization in medical ICU survivors with a primary or secondary discharge diagnosis of alcohol withdrawal. This finding highlights the potential importance of targeting longitudinal multidisciplinary care to patients with a dual diagnosis.
doi:10.1111/acer.12124
PMCID: PMC4045620  PMID: 23647435
alcohol withdrawal; alcohol use disorder; intensive care unit; rehospitalization; dual diagnosis
18.  Bronchoalveolar lavage neuregulin-1 is elevated in acute lung injury and correlates with inflammation 
The European respiratory journal  2012;41(2):396-401.
Shedding of neuregulin (NRG)-1 from the pulmonary epithelium leads to activation of the epithelial human epidermal growth factor receptor (HER)2 receptor, increased pulmonary epithelial permeability and acute lung injury (ALI). We sought to determine whether NRG-1 was detectable and elevated in bronchoalveolar lavage (BAL) and plasma from patients with ALI compared with controls and to determine whether a correlation exists between NRG-1 and inflammation and outcome in ALI.
Matched BAL and plasma samples were obtained from 23 ALI patients requiring intubation and mechanical ventilation. Control patients (n=5) included healthy volunteers. NRG-1 and indices of inflammation were measured in BAL and plasma via ELISA.
The mean±sd BAL NRG-1 concentration in ALI patients was 187.0±21.35 pg·mL−1 compared with 85.50±9.2 pg·mL−1 in controls (p=0.001). Increased BAL NRG-1 was associated with markers of inflammation, and inversely correlated with ventilator-free days (VFDs; r= −0.51, p=0.015). Plasma NRG-1 was elevated in ALI patients compared with controls (611.7±354.2 versus 25.17±19.33 pg·mL−1, p<0.001) and inversely correlated with VFDs (r= −0.51, p=0.04).
These results confirm shedding of NRG-1 in ALI and suggest that the NRG-1–HER2 pathway is active in patients with ALI.
doi:10.1183/09031936.00004912
PMCID: PMC4140244  PMID: 22599357
Acute respiratory failure; alveolar epithelium; biomarkers; inflammatory mediators
19.  Training Mentors of Clinical and Translational Research Scholars: A Randomized Controlled Trial 
Purpose
To determine whether a structured mentoring curriculum improves research mentoring skills.
Method
The authors conducted a randomized controlled trial (RCT) at 16 academic health centers (June 2010 to July 2011). Faculty mentors of trainees who were conducting clinical/translational research ≥50% of the time were eligible. The intervention was an eight-hour, case-based curriculum focused on six mentoring competencies. The primary outcome was the change in mentors’ self-reported pretest to posttest composite scores on the Mentoring Competency Assessment (MCA). Secondary outcomes included changes in the following: mentors’ awareness as measured by their self-reported retrospective change in MCA scores, mentees’ ratings of their mentors’ competency as measured by MCA scores, and mentoring behaviors as reported by mentors and their mentees.
Results
A total of 283 mentor–mentee pairs were enrolled: 144 mentors were randomized to the intervention; 139 to the control condition. Self-reported pre-/posttest change in MCA composite scores was higher for mentors in the intervention group compared with controls (P < .001). Retrospective changes in MCA composite scores between the two groups were even greater, and extended to all six subscale scores (P < .001). More intervention-group mentors reported changes in their mentoring practices than control mentors (P < .001). Mentees working with intervention-group mentors reported larger changes in retrospective MCA pre-/posttest scores (P = .003) and more changes in their mentors’ behavior (P = .002) than those paired with control mentors.
Conclusions
This RCT demonstrates that a competency-based research mentor training program can improve mentors’ skills.
doi:10.1097/ACM.0000000000000218
PMCID: PMC4121731  PMID: 24667509
20.  Alcohol Screening Scores and 90 Day Outcomes in Patients with Acute Lung Injury 
Critical care medicine  2013;41(6):1518-1525.
Objective
The effects of excess alcohol consumption (alcohol misuse) on outcomes in patients with acute lung injury (ALI) have been inconsistent, and there are no studies examining this association in the era of low tidal volume ventilation and a fluid conservative strategy. We sought to determine whether validated scores on the Alcohol Use Disorders Identification Test (AUDIT) that correspond to past year abstinence (zone 1), low-risk drinking (zone 2), mild to moderate alcohol misuse (zone 3), and severe alcohol misuse (zone 4) are associated with poor outcomes in patients with ALI.
Design
Secondary analysis.
Setting
The Acute Respiratory Distress Syndrome (ARDS) network, a consortium of 12 university centers (44 hospitals) dedicated to the conduct of multi-center clinical trials in patients with acute lung injury.
Subjects
Patients meeting consensus criteria for ALI enrolled in one of three recent ARDS network clinical trials.
Interventions
None
Measurements and Main Results
Of 1,133 patients enrolled in one of three ARDS network studies, 1,037 patients had an AUDIT score available for analysis. Alcohol misuse was common with 70 (7%) of patients having AUDIT scores in zone 3 and 129 (12%) patients in zone 4. There was a u-shaped association between validated AUDIT zones and death or persistent hospitalization at 90 days (34% in zone 1, 26% in zone 2, 27% in zone 3, 36% in zone 4; p < 0.05 for comparison of zone 1 to zone 2 and zone 4 to zone 2). In a multiple logistic regression model, there was a significantly higher odds of death or persistent hospitalization in patients in AUDIT zone 4 when compared to those in zone 2 (adjusted OR 1.70; 95% CI 1.00, 2.87; p = 0.048).
Conclusions
Severe, but not mild to moderate alcohol misuse is independently associated with an increased risk of death or persistent hospitalization at 90 days in ALI patients.
doi:10.1097/CCM.0b013e318287f1bb
PMCID: PMC4048714  PMID: 23538449
alcohol use disorders identification test; acute lung injury; alcohol use disorder; alcohol misuse; unhealthy alcohol use
21.  The fibroproliferative response in acute respiratory distress syndrome: mechanisms and clinical significance 
The European respiratory journal  2013;43(1):276-285.
Acute respiratory distress syndrome (ARDS) continues to be a major healthcare problem, affecting >190 000 people in the USA annually, with a mortality of 27–45%, depending on the severity of the illness and comorbidities. Despite advances in clinical care, particularly lung protective strategies of mechanical ventilation, most survivors experience impaired health-related quality of life for years after the acute illness. While most patients survive the acute illness, a subset of ARDS survivors develops a fibroproliferative response characterised by fibroblast accumulation and deposition of collagen and other extracellular matrix components in the lung.
Historically, the development of severe fibroproliferative lung disease has been associated with a poor prognosis with high mortality and/or prolonged ventilator dependence. More recent studies also support a relationship between the magnitude of the fibroproliferative response and long-term health-related quality of life. The factors that determine which patients develop fibroproliferative ARDS and the cellular mechanisms responsible for this pathological response are not well understood.
This article reviews our current understanding of the contribution of pulmonary dysfunction to mortality and to quality of life in survivors of ARDS, the mechanisms driving pathological fibroproliferation and potential therapeutic approaches to prevent or attenuate fibroproliferative lung disease.
doi:10.1183/09031936.00196412
PMCID: PMC4015132  PMID: 23520315
22.  Diagnosis and treatment of post-extubation dysphagia: Results from a National Survey 
Journal of critical care  2012;27(6):578-586.
Purpose
This study sought to determine the utilization of speech-language pathologist (SLPs) for the diagnosis and treatment of post-extubation dysphagia in survivors of mechanical ventilation.
Methods
We designed, validated, and mailed a survey to 1,966 inpatient SLPs who routinely evaluate patients for post-extubation dysphagia.
Results
The majority of SLP diagnostic evaluations (60%; 95% CI = 59–62%) were performed using clinical techniques with uncertain accuracy. Instrumental diagnostic tests (such as fluoroscopy and endoscopy) are more likely to be available at university than community hospitals. After adjusting for hospital size and academic affiliation, instrumental test use varied significantly by geographical region. Treatments for post-extubation dysphagia usually involved dietary adjustment (76%; 95% CI = 73–79%) and postural changes/compensatory maneuvers (86%; 95% CI = 84–88%), rather than on interventions aimed to improve swallowing function (24%; 95% CI = 21–27%).
Conclusions
SLPs frequently evaluate acute respiratory failure survivors. However, diagnostic evaluations rely mainly upon bedside techniques with uncertain accuracy. The use of instrumental tests varies by geographic location and university affiliation. Current diagnostic practices and feeding decisions for critically ill patients should be viewed with caution until further studies determine the accuracy of bedside detection methods.
doi:10.1016/j.jcrc.2012.07.016
PMCID: PMC3518658  PMID: 23084136
Mechanical Ventilation; Intratracheal Intubation; Respiratory Aspiration; Dysphagia; Swallowing Disorders
23.  Mentoring Translational Science Investigators 
doi:10.1001/jama.2012.14367
PMCID: PMC3767996  PMID: 23168821
24.  The protective role of laparoscopic antireflux surgery against aspiration of pepsin after lung transplantation 
Surgery  2011;150(4):598-606.
Background
The goal of this study was to determine, in lung transplant patients, if laparoscopic antireflux surgery (LARS) is an effective means to prevent aspiration as defined by the presence of pepsin in the bronchoalveolar lavage fluid (BALF).
Methods
Between September 2009 and November 2010, we collected BALF from 64 lung transplant patients at multiple routine surveillance assessments for acute cellular rejection, or when clinically indicated for diagnostic purposes. The BALF was tested for pepsin by enzyme-linked immunosorbent assay (ELISA). We then compared pepsin concentrations in the BALF of healthy controls (n = 11) and lung transplant patients with and without gastroesophageal reflux disease (GERD) on pH-monitoring (n = 8 and n = 12, respectively), and after treatment of GERD by LARS (n = 19). Time to the development of bronchiolitis obliterans syndrome was contrasted between groups based on GERD status or the presence of pepsin in the BALF.
Results
We found that lung transplant patients with GERD had more pepsin in their BALF than lung transplant patients who underwent LARS (P = .029), and that pepsin was undetectable in the BALF of controls. Moreover, those with more pepsin had quicker progression to BOS and more acute rejection episodes.
Conclusion
This study compared pepsin in the BALF from lung transplant patients with and without LARS. Our data show that: (1) the detection of pepsin in the BALF proves aspiration because it is not present in healthy volunteers, and (2) LARS appears effective as a measure to prevent the aspiration of gastroesophageal refluxate in the lung transplant population. We believe that these findings provide a mechanism for those studies suggesting that LARS may prevent nonallogenic injury to the transplanted lungs from aspiration of gastroesophageal contents.
doi:10.1016/j.surg.2011.07.053
PMCID: PMC3694415  PMID: 22000170
25.  Post-extubation dysphagia is associated with longer hospitalization in survivors of critical illness with neurologic impairment 
Critical Care  2013;17(3):R119.
Introduction
Critically ill patients can develop acute respiratory failure requiring endotracheal intubation. Swallowing dysfunction after liberation from mechanical ventilation, also known as post-extubation dysphagia, is common and deleterious among patients without neurologic disease. However, the risk factors associated with the development of post-extubation dysphagia and its effect on hospital lengthofstay in critically ill patients with neurologic disorders remains relatively unexplored.
Methods
We conducted a retrospective, observational cohort study from 2008 to 2010 of patients with neurologic impairment who required mechanical ventilation and subsequently received a bedside swallow evaluation (BSE) by a speech-language pathologist.
Results
A BSE was performed after mechanical ventilation in 25% (630/2,484) of all patients. In the 184 patients with neurologic impairment, post-extubation dysphagia was present in 93% (171/184), and was classified as mild, moderate, or severe in 34% (62/184), 26% (48/184), and 33% (61/184), respectively. In univariate analyses, statistically significant risk factors for moderate/severe dysphagia included longer durations of mechanical ventilation and the presence of a tracheostomy. In multivariate analysis, adjusting for age, tracheostomy, cerebrovascular disease, and severity of illness, mechanical ventilation for >7 days remained independently associated with moderate/severe dysphagia (adjusted odds ratio = 4.48 (95%confidence interval = 2.14 to 9.81), P<0.01). The presence of moderate/severe dysphagia was also significantly associated with prolonged hospital lengthofstay, discharge status, and surgical placement of feeding tubes. When adjusting for age, severity of illness, and tracheostomy, patients with moderate/severe dysphagia stayed in the hospital 4.32 days longer after their initial BSE than patients with none/mild dysphagia (95% confidence interval = 3.04 to 5.60 days, P <0.01).
Conclusion
In a cohort of critically ill patients with neurologic impairment, longer duration of mechanical ventilation is independently associated with post-extubation dysphagia, and the development of post-extubation dysphagia is independently associated with a longer hospital length of stay after the initial BSE.
doi:10.1186/cc12791
PMCID: PMC4057203  PMID: 23786755
mechanical ventilation; intubation; intratracheal; swallowing disorders; dysphagia; aspiration; respiratory

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