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Government of the United States of America

governmentWashington, District of Columbia, United States

Research output, citation impact, and the most-cited recent papers from Government of the United States of America (United States). Aggregated across the NobleBlocks index of 300M+ scholarly works.

Total works
8.7K
Citations
204.4K
h-index
168
i10-index
2.9K
Also known as
Government of the United States of America

Top-cited papers from Government of the United States of America

The Twentieth Century Reanalysis Project
Gilbert P. Compo, Jeffrey S. Whitaker, Prashant D. Sardeshmukh, N. Matsui +4 more
2011· Quarterly Journal of the Royal Meteorological Society3.7Kdoi:10.1002/qj.776

Abstract The Twentieth Century Reanalysis (20CR) project is an international effort to produce a comprehensive global atmospheric circulation dataset spanning the twentieth century, assimilating only surface pressure reports and using observed monthly sea‐surface temperature and sea‐ice distributions as boundary conditions. It is chiefly motivated by a need to provide an observational dataset with quantified uncertainties for validations of climate model simulations of the twentieth century on all time‐scales, with emphasis on the statistics of daily weather. It uses an Ensemble Kalman Filter data assimilation method with background ‘first guess’ fields supplied by an ensemble of forecasts from a global numerical weather prediction model. This directly yields a global analysis every 6 hours as the most likely state of the atmosphere, and also an uncertainty estimate of that analysis. The 20CR dataset provides the first estimates of global tropospheric variability, and of the dataset's time‐varying quality, from 1871 to the present at 6‐hourly temporal and 2° spatial resolutions. Intercomparisons with independent radiosonde data indicate that the reanalyses are generally of high quality. The quality in the extratropical Northern Hemisphere throughout the century is similar to that of current three‐day operational NWP forecasts. Intercomparisons over the second half‐century of these surface‐based reanalyses with other reanalyses that also make use of upper‐air and satellite data are equally encouraging. It is anticipated that the 20CR dataset will be a valuable resource to the climate research community for both model validations and diagnostic studies. Some surprising results are already evident. For instance, the long‐term trends of indices representing the North Atlantic Oscillation, the tropical Pacific Walker Circulation, and the Pacific–North American pattern are weak or non‐existent over the full period of record. The long‐term trends of zonally averaged precipitation minus evaporation also differ in character from those in climate model simulations of the twentieth century. Copyright © 2011 Royal Meteorological Society and Crown Copyright.

2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS)
Alexander R. Lyon, Teresa López‐Fernández, Liam S. Couch, Riccardo Asteggiano +4 more
2022· European Heart Journal2.7Kdoi:10.1093/eurheartj/ehac244

International audience

Corporate disclosure quality and the cost of debt.
Partha Pratim Sengupta
1998· The Accounting Review930doi:10.2308/tar-1325290

Abstract This paper provides evidence that firms with high disclosure quality ratings from financial analysis enjoy a lower effective interest cost of issuing debt. This findings is consistent with the argument that a policy of timely and detailed disclosures reduces lenders' and underwriters' perception of default risk for the disclosing firm, reducing its constant of debt. The results also indicate that the relative importance of disclosures is greater in situations where there is greater market uncertainty about the firm as reflected by the variance of stock returns. Since debt financial is an important source of external financing for publicly traded firms, the results have important implications on our understanding of the motives and consequences of corporate disclosures.

Military TBI During the Iraq and Afghanistan Wars
Deborah L. Warden
2006· Journal of Head Trauma Rehabilitation813doi:10.1097/00001199-200609000-00004

Traumatic brain injury (TBI) is an important source of morbidity in the Iraq and Afghanistan wars. Although penetrating brain injuries are more readily identified, closed brain injuries occur more commonly. Explosion or blast injury is the most common cause of war injuries. The contribution of the primary blast wave (primary blast injury) in brain injury is an area of active research. Lessons learned from the sports concussion and civilian mild TBI literature are useful. Individuals with TBI and posttraumatic stress disorder require treatment of both conditions. Families and communities need to be cognizant of the needs of these returning veterans.

Is China a Status Quo Power?
Alastair Iain Johnston
2003· International Security723doi:10.1162/016228803321951081

April 01 2003 Is China a Status Quo Power? Alastair Iain Johnston Alastair Iain Johnston Laine Professor of China in World Affairs in the Government Department at Harvard University. Search for other works by this author on: This Site Google Scholar Author and Article Information Alastair Iain Johnston Laine Professor of China in World Affairs in the Government Department at Harvard University. Online ISSN: 1531-4804 Print ISSN: 0162-2889 © 2003 by the President and Fellows of Harvard College and the Massachusetts Institute of Technology2003 International Security (2003) 27 (4): 5–56. https://doi.org/10.1162/016228803321951081 Cite Icon Cite Permissions Share Icon Share Facebook Twitter LinkedIn Email Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Search Site Citation Alastair Iain Johnston; Is China a Status Quo Power?. International Security 2003; 27 (4): 5–56. doi: https://doi.org/10.1162/016228803321951081 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsInternational Security Search Advanced Search This content is only available as a PDF. © 2003 by the President and Fellows of Harvard College and the Massachusetts Institute of Technology2003 Article PDF first page preview Close Modal You do not currently have access to this content.

Is Anybody Still a Realist?
Jeffrey W. Legro, Andrew Moravcsik
1999· International Security713doi:10.1162/016228899560130

October 01 1999 Is Anybody Still a Realist? Jeffrey W. Legro, Jeffrey W. Legro Associate Professor of Government and Foreign Affairs, University of Virginia. Search for other works by this author on: This Site Google Scholar Andrew Moravcsik Andrew Moravcsik Professor of Government, Harvard University. Search for other works by this author on: This Site Google Scholar Author and Article Information Jeffrey W. Legro Associate Professor of Government and Foreign Affairs, University of Virginia. Andrew Moravcsik Professor of Government, Harvard University. Online Issn: 1531-4804 Print Issn: 0162-2889 © 1999 President and Fellows of Harvard College and the Massachusetts Institute of Technology1999 International Security (1999) 24 (2): 5–55. https://doi.org/10.1162/016228899560130 Cite Icon Cite Permissions Share Icon Share Facebook Twitter LinkedIn MailTo Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Search Site Citation Jeffrey W. Legro, Andrew Moravcsik; Is Anybody Still a Realist?. International Security 1999; 24 (2): 5–55. doi: https://doi.org/10.1162/016228899560130 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsInternational Security Search Advanced Search This content is only available as a PDF. © 1999 President and Fellows of Harvard College and the Massachusetts Institute of Technology1999 Article PDF first page preview Close Modal You do not currently have access to this content.

2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS)
Alexander R. Lyon, Teresa López‐Fernández, Liam S. Couch, Riccardo Asteggiano +4 more
2022· European Heart Journal - Cardiovascular Imaging484doi:10.1093/ehjci/jeac106

peer reviewed

Economic Interdependence and War: A Theory of Trade Expectations
Dale C. Copeland
1996· International Security422doi:10.1162/isec.20.4.5

April 01 1996 Economic Interdependence and War: A Theory of Trade Expectations Dale C. Copeland Dale C. Copeland Dale C. Copeland is Assistant Professor in the Department of Government and Foreign Affairs at the University of Virginia. Search for other works by this author on: This Site Google Scholar Author and Article Information Dale C. Copeland Dale C. Copeland is Assistant Professor in the Department of Government and Foreign Affairs at the University of Virginia. Online Issn: 1531-4804 Print Issn: 0162-2889 © 1996 by the President and Fellows of Harvard College and the Massachusetts Institute of Technology.1996 International Security (1996) 20 (4): 5–41. https://doi.org/10.1162/isec.20.4.5 Cite Icon Cite Permissions Share Icon Share Twitter LinkedIn Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Search Site Citation Dale C. Copeland; Economic Interdependence and War: A Theory of Trade Expectations. International Security 1996; 20 (4): 5–41. doi: https://doi.org/10.1162/isec.20.4.5 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsInternational Security Search Advanced Search This content is only available as a PDF. © 1996 by the President and Fellows of Harvard College and the Massachusetts Institute of Technology.1996 Article PDF first page preview Close Modal You do not currently have access to this content.

Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012)
Susan H. Eshleman, Martin Mracna, Laura Guay, Martina Deseyve +4 more
2001· AIDS421doi:10.1097/00002030-200110190-00006

OBJECTIVE: To examine the emergence and fading of NVP resistance (NVP(R)) mutations in HIV-1-infected Ugandan women and infants who received single dose NVP to prevent HIV-1 vertical transmission. DESIGN: We examined NVP(R) in women and infants who received NVP in the HIVNET 012 clinical trial, including 41 out of 48 women with infected infants, 70 randomly-selected women with uninfected infants, and 33 out of 49 infected infants. METHODS: Plasma HIV-1 was analyzed using the Applied Biosystems ViroSeq HIV-1 Genotyping System. RESULTS: NVP(R) mutations were detected in 21 out of 111 (19%) women tested 6-8 weeks after delivery. The rate of NVP(R) was similar among women whose infants were or were not HIV-1 infected. K103N was the most common mutation detected. NVP(R) mutations faded from detection within 12-24 months in all 11 evaluable women. High baseline viral load and low baseline CD4 cell count were associated with development of NVP(R). NVP(R) mutations were detected in 11 out of 24 (46%) evaluable infants who were infected by 6-8 weeks of age. The most common NVP(R) mutation detected in infants was Y181C. Those mutations faded from detection by 12 months of age in all seven evaluable infants. Of nine evaluable infants with late HIV-1 infection, only one had evidence of NVP(R). CONCLUSIONS: NVP(R) was detected more frequently in infants than women following NVP prophylaxis, and different patterns of NVP(R) mutations were detected in women versus infants. NVP(R) was detected infrequently in infants with late HIV-1 infection. NVP-resistant HIV-1 faded from detection in women and infants over time.

Practical Use of Emergency Tourniquets to Stop Bleeding in Major Limb Trauma
John F Kragh, James Walters, David G. Baer, Charles J. Fox +3 more
2008· The Journal of Trauma: Injury, Infection, and Critical Care403doi:10.1097/ta.0b013e31816086b1

BACKGROUND: Previously we showed that tourniquets were lifesaving devices in the current war. Few studies, however, describe their actual morbidity in combat casualties. The purpose of this study was to measure tourniquet use and complications. METHODS: A prospective survey of casualties who required tourniquets was performed at a combat support hospital in Baghdad during 7 months in 2006. Patients were evaluated for tourniquet use, limb outcome, and morbidity. We identified potential morbidities from the literature and looked for them prospectively. The protocol was approved by the institutional review board. RESULTS: The 232 patients had 428 tourniquets applied on 309 injured limbs. The most effective tourniquets were the Emergency Medical Tourniquet (92%) and the Combat Application Tourniquet (79%). Four patients (1.7%) sustained transient nerve palsy at the level of the tourniquet, whereas six had palsies at the wound level. No association was seen between tourniquet time and morbidity. There was no apparent association of total tourniquet time and morbidity (clots, myonecrosis, rigor, pain, palsies, renal failure, amputation, and fasciotomy). No amputations resulted solely from tourniquet use. However, six (2.6%) casualties with eight preexisting traumatic amputation injuries then had completion surgical amputations and also had tourniquets on for >2 hours. The rate of limbs with fasciotomies with tourniquet time <or=2 hours was 28% (75 of 272) and >2 hours was 36% (9 of 25, p = 0.4). CONCLUSIONS: Morbidity risk was low, and there was a positive risk benefit ratio in light of the survival benefit. No limbs were lost because of tourniquet use, and tourniquet duration was not associated with increased morbidity. Education for early military tourniquet use should continue.

Volumetric Muscle Loss
Brian F. Grogan, Joseph R. Hsu
2011· Journal of the American Academy of Orthopaedic Surgeons396doi:10.5435/00124635-201102001-00007

Prevention of infection, as well as bone covering and healing, is paramount in the management of limb injury with associated muscle injury. Volumetric muscle loss (VML) is the traumatic or surgical loss of skeletal muscle with resultant functional impairment. No standardized evaluation protocol exists for the characterization and quantification of VML. Clinical photographs and video recordings, range of motion measurements, manual muscle strength testing, and isokinetic muscle function testing may prove to be useful in documenting VML. Current treatment options include functional free muscle transfer and the use of advanced bracing designs. Advances in powered bracing and regenerative medicine may one day provide additional therapeutic options. Further research on VML is warranted.

Success Matters: Casualty Sensitivity and the War in Iraq
Christopher Gelpi, Peter D. Feaver, Jason Reifler
2006· International Security393doi:10.1162/isec.2005.30.3.7

Since the Vietnam War, U.S. policymakers have worried that the American public will support military operations only if the human costs of the war, as measured in combat casualties, are minimal. Although the public is rightly averse to suffering casualties, the level of popular sensitivity to U.S. military casualties depends critically on the context in which those losses occur. The public's tolerance for the human costs of war is primarily shaped by the intersection of two crucial factors: beliefs about the rightness or wrongness of the war, and beliefs about the war's likely success. The impact of each belief depends upon the other. Ultimately, however, beliefs about the likelihood of success matter most in determining the public's willingness to tolerate U.S. military deaths in combat. A reanalysis of publicly available polls and a detailed analysis of a series of polls designed by the authors to tap into public attitudes on casualties support this conclusion.

WILLINGNESS‐TO‐PAY FOR CRIME CONTROL PROGRAMS*
Mark A. Cohen, Roland T. Rust, Sara Steen, Simon T. Tidd
2004· Criminology391doi:10.1111/j.1745-9125.2004.tb00514.x

This paper reports on a new methodology to estimate the “cost of crime.” It is adapted from the contingent valuation method used in the environmental economics literature and is itself used to estimate the public's willingness to pay for crime control programs. In a nationally representative sample of 1,300 U.S. residents, we found that the typical household would be willing to pay between $100 and $150 per year for programs that reduced specific crimes by 10 percent in their communities. This willingness amounts, collectively, to approximately $25,000 per burglary, $70,000 per serious assault, $232,000 per armed

The Myth of Cyberwar: Bringing War in Cyberspace Back Down to Earth
Erik Gartzke
2013· International Security375doi:10.1162/isec_a_00136

Cyberwar has been described as a revolution in military affairs, a transformation of technology and doctrine capable of overturning the prevailing world order. This characterization of the threat from cyberwar, however, reflects a common tendency to conflate means and ends; studying what could happen in cyberspace (or anywhere else) makes little sense without considering how conflict over the internet is going to realize objectives commonly addressed by terrestrial warfare. To supplant established modes of conflict, cyberwar must be capable of furthering the political ends to which force or threats of force are commonly applied, something that in major respects cyberwar fails to do. As such, conflict over the internet is much more likely to serve as an adjunct to, rather than a substitute for, existing modes of terrestrial force. Indeed, rather than threatening existing political hierarchies, cyberwar is much more likely to simply augment the advantages of status quo powers.

Differences in Mortality between Elderly and Younger Adult Trauma Patients
Philip W. Perdue, Dorraine D. Watts, Christoph Kaufmann, Arthur L. Trask
1998372doi:10.1097/00005373-199810000-00034

BACKGROUND: Elderly patients suffer higher mortality rates after trauma than younger patients. This increased mortality is attributable to age, preexisting disease, and complications as well as injury severity. METHODS: Records from 5,139 adult patients from a Level I trauma center were retrospectively reviewed. Injury Severity Score (ISS), Revised Trauma Score (RTS), early mortality (<24 hours), and late mortality (>24 hours) were determined for elderly (> or =65 years) and younger (16-64 years) patients. Preexisting diseases and complications were identified by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis coding. RESULTS: Mortality in elderly patients was twice that in younger patients despite equivalent injury severity (p < 0.001), and elderly patients were more likely to suffer later death than younger patients (p < 0.005). The prevalence of preexisting disease was greater in the elderly, as was the incidence of complications. Using logistic regression, ISS, RTS, preexisting cardiovascular or liver disease, the development of cardiac, renal, or infectious complications, and geriatric status were all independently predictive of late mortality (p < 0.05). CONCLUSION: Elderly trauma patients more frequently suffer late mortality than younger patients because of the combination of injury and increased preexisting disease and complications after injury. Aggressive treatment of the elderly trauma patient is warranted; however, in the face of significant preexisting disease or complications, survival is less likely. Predictive models of survival can be developed, taking into account preexisting disease and complications as well as admission parameters such as age, ISS, and RTS, and specific risk of mortality quantitated.

Tropical cyclone spin‐up revisited
Roger K. Smith, Michael T. Montgomery, Nguyễn Văn Sáng
2009· Quarterly Journal of the Royal Meteorological Society339doi:10.1002/qj.428

Abstract We present numerical experiments to investigate axisymmetric interpretations of tropical cyclone spin‐up in a three‐dimensional model. Two mechanisms are identified for the spin‐up of the mean tangential circulation. The first involves the convergence of absolute angular momentum above the boundary layer and is a mechanism to spin up the outer circulation, i.e. to increase the vortex size. The second involves the convergence of absolute angular momentum within the boundary layer and is a mechanism to spin up the inner core. It is associated with the development of supergradient wind speeds in the boundary layer. The existence of these two mechanisms provides a plausible physical explanation for certain long‐standing observations of typhoons by Weatherford and Gray, which indicate that inner‐core changes in the azimuthal‐mean tangential wind speed often occur independently from those in the outer core. The unbalanced dynamics in the inner‐core region are important in determining the maximum radial and tangential flow speeds that can be attained, and therefore important in determining the azimuthal‐mean intensity of the vortex. We illustrate the importance of unbalanced flow in the boundary layer with a simple thought experiment. The analyses and interpretations presented are novel and support a recent hypothesis of the boundary layer in the inner‐core region. Copyright © 2009 Royal Meteorological Society

The Hill-Sachs Lesion: Diagnosis, Classification, and Management
Matthew T. Provencher, Rachel M. Frank, Lance E. LeClere, Paul Metzger +3 more
2012· Journal of the American Academy of Orthopaedic Surgeons332doi:10.5435/jaaos-20-04-242

The Hill-Sachs lesion is an osseous defect of the humeral head that is typically associated with anterior shoulder instability. The incidence of these lesions in the setting of glenohumeral instability is relatively high and approaches 100% in persons with recurrent anterior shoulder instability. Reverse Hill-Sachs lesion has been described in patients with posterior shoulder instability. Glenoid bone loss is typically associated with the Hill-Sachs lesion in patients with recurrent anterior shoulder instability. The lesion is a bipolar injury, and identification of concomitant glenoid bone loss is essential to optimize clinical outcome. Other pathology (eg, Bankart tear, labral or capsular injuries) must be identified, as well. Treatment is dictated by subjective and objective findings of shoulder instability and radiographic findings. Nonsurgical management, including focused rehabilitation, is acceptable in cases of small bony defects and nonengaging lesions in which the glenohumeral joint remains stable during desired activities. Surgical options include arthroscopic and open techniques.

Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation1,2
Herwig‐Ulf Meier‐Kriesche, Rajendra Baliga, Bruce Kaplan
2003· Transplantation324doi:10.1097/01.tp.0000061602.03327.e2

BACKGROUND: Chronic kidney disease is thought to be a potential risk factor for cardiovascular death. In renal-allograft recipients, cardiovascular disease is the most significant cause of death. The purpose of this study was to investigate if renal function has a significant role in determining the risk for cardiovascular death in renal-allograft recipients. METHODS: We analyzed 58,900 adult patients registered in the United States Renal Data System who received a primary renal transplant between 1988 and 1998 and who had at least 1 year of graft survival. The primary study endpoint was death from a cardiovascular event beyond 1 year of transplantation. Secondary endpoints were death caused by infections and malignancy-related deaths. Cox proportional-hazard models were used to estimate the effect of renal function on cardiovascular death, infectious death, and malignancy-related death while correcting for potential confounding variables, such as donor and recipient age, gender, race, cause of end-stage renal disease, length of dialysis before transplantation, year of transplantation, donor source and age, delayed graft function, and immunosuppressive regimen. RESULTS: Serum creatinine values at 1 year after transplantation were strongly associated with the risk for cardiovascular death. Above a serum creatinine value of 1.5 mg/dL, there was a significant and progressive increase in the risk for cardiovascular death. The risk of cardiovascular death was significantly higher when patients who lost allograft function were included in the analysis. There was an association between worsening renal function and infectious death, but there was no association between renal function and malignancy-related death. CONCLUSION: Serum creatinine at 1 year is strongly associated with the incidence of cardiovascular death independent of known risk factors.

High-frequency oscillatory ventilation for adult respiratory distress syndrome-A pilot study
Peter Fort, Christopher J. Farmer, Jan Westerman, Jay A. Johannigman +3 more
1997· Critical Care Medicine322doi:10.1097/00003246-199706000-00008

OBJECTIVE: To evaluate the safety and effectiveness of high-frequency oscillatory ventilation using a protocol designed to recruit and maintain optimal lung volume in patients with severe adult respiratory distress syndrome (ARDS). SETTING: Surgical and medical intensive care units in a tertiary care, military teaching hospital. DESIGN: A prospective, clinical study. PATIENTS: Seventeen patients, 17 yrs to 83 yrs of age, with severe ARDS (Lung Injury Score of 3.81 +/- 0.23) failing inverse ratio mechanical conventional ventilation (PaO2/FiO2 ratio of 68.6 +/- 21.6, peak inspiratory pressure of 54.3 +/- 12.7 cm H2O, positive end-expiratory pressure of 18.2 +/- 6.9 cm H2O). INTERVENTIONS: High-frequency oscillatory ventilation was instituted after varying periods of conventional ventilation (5.12 +/- 4.3 days). We employed lung volume recruitment strategy that consisted of incremental increases in mean airway pressure to achieve a PaO2 of > or = 60 torr (> or = 8.0 kPa), with an FiO2 of < or = 0.6. MEASUREMENTS AND MAIN RESULTS: High-frequency oscillator ventilator settings (FiO2, mean airway pressure, pressure amplitude of oscillation [delta P] frequency) and hemodynamic parameters (cardiac output, oxygen delivery [DO2]), mean systemic and pulmonary arterial pressures, and the oxygenation index (oxygenation index = [FiO2 x mean airway pressure x 100]/PaO2) were monitored during the transition to high-frequency oscillatory ventilation and throughout the course of the high-frequency protocol. Thirteen patients demonstrated improved gas exchange and an overall improvement in PaO2/FiO2 ratio (p < .02). Reductions in the oxygenation index (p < .01) and FiO2 (p < .02) at 12, 24, and 48 hrs after starting high-frequency oscillatory ventilation were observed. No significant compromise in cardiac output or DO2 was observed, despite a significant increase in mean airway pressure (31.2 +/- 10.3 to 34.0 +/- 6.7 cm H2O, p < .05) on high-frequency oscillatory ventilation. The overall survival rate at 30 days was 47%. A greater number of pretreatment days on conventional ventilation (p < .009) and an entry oxygenation index of > 47 (sensitivity 100%, specificity 100%) were associated with mortality. CONCLUSIONS: High-frequency oscillatory ventilation is both safe and effective in adult patients with severe ARDS failing conventional ventilation. A lung volume recruitment strategy during high-frequency oscillatory ventilation produced improved gas exchange without a compromise in DO2. These results are encouraging and support the need for a prospective, randomized trial of algorithm-controlled conventional ventilation vs. high-frequency oscillatory ventilation for adults with severe ARDS.

Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation
Matthew D. Wilkerson, Xiaoying Yin, Vonn Walter, Ni Zhao +4 more
2012· PLoS ONE303doi:10.1371/journal.pone.0036530

BACKGROUND: Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors. METHODOLOGY/PRINCIPAL FINDINGS: The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes. CONCLUSIONS/ SIGNIFICANCE: The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.