Showing papers by "University of Colorado Denver published in 2011"
Université Paris-Saclay1, Cross Cancer Institute2, University of British Columbia3, Nevada Cancer Institute4, Université de Montréal5, Cardiff University6, University of Colorado Denver7, Baylor University Medical Center8, University of Calgary9, Sarah Cannon Research Institute10, University of California, San Francisco11, Memorial Sloan Kettering Cancer Center12
TL;DR: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy.
Abstract: BACKGROUND Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. METHODS We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. RESULTS After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group. CONCLUSIONS The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.)
3,875 citations
TL;DR: Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizuab administered monthly, although the comparison between bevacizumAB as needed and monthly bevicizumabs was inconclusive.
Abstract: Background Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. Methods In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart. Results Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. Conclusions At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.).
2,425 citations
Harvard University1, Cincinnati Children's Hospital Medical Center2, Duke University3, University of Arkansas for Medical Sciences4, Icahn School of Medicine at Mount Sinai5, Johns Hopkins University School of Medicine6, National Institutes of Health7, St Mary's Hospital8, University of Southampton9, LSU Health Sciences Center Shreveport10, University of Rochester Medical Center11, Rutgers University12, University of California, San Diego13, Boston Children's Hospital14, University of Colorado Denver15, Oregon Health & Science University16, University of Tennessee Health Science Center17, Food and Drug Administration18, University of California, Irvine19, Scripps Health20, University of Manitoba21, Children's National Medical Center22, University of Minnesota23, University of Rochester24
TL;DR: The National Institute of Allergy and Infectious Diseases, working with 34 professional organizations, federal agencies, and patient advocacy groups, led the development of clinical guidelines for the diagnosis and management of food allergy, which include a consensus definition for food allergy.
Abstract: Food allergy is an important public health problem that affects children and adults and may be increasing in prevalence. Despite the risk of severe allergic reactions and even death, there is no current treatment for food allergy: the disease can only be managed by allergen avoidance or treatment of symptoms. The diagnosis and management of food allergy also may vary from one clinical practice setting to another. Finally, because patients frequently confuse nonallergic food reactions, such as food intolerance, with food allergies, there is an unfounded belief among the public that food allergy prevalence is higher than it truly is. In response to these concerns, the National Institute of Allergy and Infectious Diseases, working with 34 professional organizations, federal agencies, and patient advocacy groups, led the development of clinical guidelines for the diagnosis and management of food allergy. These Guidelines are intended for use by a wide variety of health care professionals, including family practice physicians, clinical specialists, and nurse practitioners. The Guidelines include a consensus definition for food allergy, discuss comorbid conditions often associated with food allergy, and focus on both IgE-mediated and non-IgE-mediated reactions to food. Topics addressed include the epidemiology, natural history, diagnosis, and management of food allergy, as well as the management of severe symptoms and anaphylaxis. These Guidelines provide 43 concise clinical recommendations and additional guidance on points of current controversy in patient management. They also identify gaps in the current scientific knowledge to be addressed through future research.
2,014 citations
TL;DR: The spectrum of engagement in care for HIV-infected individuals in the United States is reviewed and this information is applied to help understand the magnitude of the challenges that pooragement in care will pose to test-and-treat strategies for HIV prevention.
Abstract: For individuals with human immunodeficiency virus (HIV) infection to fully benefit from potent combination antiretroviral therapy, they need to know that they are HIV infected, be engaged in regular HIV care, and receive and adhere to effective antiretroviral therapy. Test-and-treat strategies for HIV prevention posit that expanded testing and earlier treatment of HIV infection could markedly decrease ongoing HIV transmission, stemming the HIV epidemic. However, poor engagement in care for HIV-infected individuals will substantially limit the effectiveness of test-and-treat strategies. We review the spectrum of engagement in care for HIVinfected individuals in the United States and apply this information to help understand the magnitude of the challenges that poor engagement in care will pose to test-and-treat strategies for HIV prevention.
1,746 citations
TL;DR: This review deals with emerging evidence of an association between systemic or local hypoxia and inflammation in a variety of diseases and points to new ways of treating inflammatory disorders or conditions such as certain cancers with intralesional Hypoxia.
Abstract: This review deals with emerging evidence of an association between systemic or local hypoxia and inflammation in a variety of diseases. The evidence points to new ways of treating inflammatory disorders or conditions such as certain cancers with intralesional hypoxia.
1,603 citations
Cleveland Clinic1, University of Texas Health Science Center at San Antonio2, Fred Hutchinson Cancer Research Center3, University of Colorado Denver4, National Institutes of Health5, Harvard University6, University of Texas MD Anderson Cancer Center7, Mayo Clinic8, Duke University9, University of Toronto10, University of California, San Diego11, University of Western Ontario12, University of California, Irvine13, University of Michigan14
TL;DR: Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men in relatively healthy men.
Abstract: Context The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer. Objective To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men. Design, Setting, and Participants A total of 35 533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men and 55 years or older for all others. The primary analysis included 34 887 men who were randomly assigned to 1 of 4 treatment groups: 8752 to receive selenium; 8737, vitamin E; 8702, both agents, and 8696, placebo. Analysis reflect the final data collected by the study sites on their participants through July 5, 2011. Interventions Oral selenium (200 μg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years. Main Outcome Measures Prostate cancer incidence. Results This report includes 54 464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination. Conclusion Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men. Trial Registration Clinicaltrials.gov Identifier: NCT00006392
1,448 citations
TL;DR: The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens and systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation.
Abstract: The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.
1,147 citations
TL;DR: Science Inquiry provides a forum to facilitate the ongoing process of questioning and evaluating practice, presents informed practice based on available data, and innovates new practices through research and experimental learning.
Abstract: Column Editor: Lauren Clark
Scientific Inquiry provides a forum to facilitate the ongoing process of questioning and evaluating practice, presents informed practice based on available data, and innovates new practices through research and experimental learning.
1,075 citations
University of Utah1, University of Alabama2, National Institutes of Health3, Henry Ford Health System4, Georgetown University5, Marshfield Clinic6, University of Colorado Denver7, University of Minnesota8, Washington University in St. Louis9, University of Pittsburgh10, University of California, Los Angeles11, Westat12, University of Toronto13
TL;DR: Among women in the general US population, simultaneous screening with CA-125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality.
Abstract: Context Screening for ovarian cancer with cancer antigen 125 (CA-125) and transvaginal ultrasound has an unknown effect on mortality. Objective To evaluate the effect of screening for ovarian cancer on mortality in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Design, Setting, and Participants Randomized controlled trial of 78 216 women aged 55 to 74 years assigned to undergo either annual screening (n = 39 105) or usual care (n = 39 111) at 10 screening centers across the United States between November 1993 and July 2001. Intervention The intervention group was offered annual screening with CA-125 for 6 years and transvaginal ultrasound for 4 years. Participants and their health care practitioners received the screening test results and managed evaluation of abnormal results. The usual care group was not offered annual screening with CA-125 for 6 years or transvaginal ultrasound but received their usual medical care. Participants were followed up for a maximum of 13 years (median [range], 12.4 years [10.9-13.0 years]) for cancer diagnoses and death until February 28, 2010. Main Outcome Measures Mortality from ovarian cancer, including primary peritoneal and fallopian tube cancers. Secondary outcomes included ovarian cancer incidence and complications associated with screening examinations and diagnostic procedures. Results Ovarian cancer was diagnosed in 212 women (5.7 per 10 000 person-years) in the intervention group and 176 (4.7 per 10 000 person-years) in the usual care group (rate ratio [RR], 1.21; 95% confidence interval [CI], 0.99-1.48). There were 118 deaths caused by ovarian cancer (3.1 per 10 000 person-years) in the intervention group and 100 deaths (2.6 per 10 000 person-years) in the usual care group (mortality RR, 1.18; 95% CI, 0.82-1.71). Of 3285 women with false-positive results, 1080 underwent surgical follow-up; of whom, 163 women experienced at least 1 serious complication (15%). There were 2924 deaths due to other causes (excluding ovarian, colorectal, and lung cancer) (76.6 per 10 000 person-years) in the intervention group and 2914 deaths (76.2 per 10 000 person-years) in the usual care group (RR, 1.01; 95% CI, 0.96-1.06). Conclusions Among women in the general US population, simultaneous screening with CA-125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality. Diagnostic evaluation following a false-positive screening test result was associated with complications. Trial Registration clinicaltrials.gov Identifier: NCT00002540
1,073 citations
TL;DR: CPDGene will provide important new information about genetic factors in COPD, and will characterize the disease process using high resolution CT scans, which will potentially permit earlier diagnosis of this disease and may lead to the development of treatments to modify progression.
Abstract: Background: COPDGene is a multicenter observational study designed to identify genetic factors associated with COPD. It will also characterize chest CT phenotypes in COPD subjects, including assessment of emphysema, gas trapping, and airway wall thickening. Finally, subtypes of COPD based on these phenotypes will be used in a comprehensive genome-wide study to identify COPD susceptibility genes. Methods/Results: COPDGene will enroll 10,000 smokers with and without COPD across the GOLD stages. Both Non-Hispanic white and African-American subjects are included in the cohort. Inspiratory and expiratory chest CT scans will be obtained on all participants. In addition to the cross-sectional enrollment process, these subjects will be followed regularly for longitudinal studies. A genome-wide association study (GWAS) will be done on an initial group of 4000 subjects to identify genetic variants associated with case-control status and several quantitative phenotypes related to COPD. The initial findings w...
1,050 citations
Constantine A. Gatsonis1, Denise R. Aberle2, Christine D. Berg, William C. Black3 +1333 more•Institutions (31)
TL;DR: The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer.
Abstract: The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography (CT) with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer, which is the leading cause of cancer-related death in the United States Five-year survival rates approach 70% with surgical resection of stage IA disease; however, more than 75% of individuals have incurable locally advanced or metastatic disease, the latter having a 5-year survival of less than 5% It is plausible that treatment should be more effective and the likelihood of death decreased if asymptomatic lung cancer is detected through screening early enough in its preclinical phase For these reasons, there is intense interest and intuitive appeal in lung cancer screening with low-dose CT The use of survival as the determinant of screening effectiveness is, however, confounded by the well-described biases of lead time, length, and overdiagnosis Despite previous attempts, no test has been shown to reduce lung cancer mortality, an endpoint that circumvents screening biases and provides a definitive measure of benefit when assessed in a randomized controlled trial that enables comparison of mortality rates between screened individuals and a control group that does not undergo the screening intervention of interest The NLST is such a trial The rationale for and design of the NLST are presented
University of Colorado Denver1, Denver Health Medical Center2, University of Minnesota3, University of Alabama at Birmingham4, University of California, Los Angeles5, Veterans Health Administration6, Temple University7, University of Michigan8, University of California, San Francisco9, Regions Hospital10, Mayo Clinic11, University of Pittsburgh12, University of Maryland, Baltimore13, University of Manitoba14
TL;DR: Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects.
Abstract: A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exac erbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among par ticipants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerba tions per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P = 0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George’s Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithro mycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P = 0.004); the percentage of participants with more than the minimal clinically important difference of −4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P = 0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P = 0.04). Conclusions Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.)
TL;DR: The biology of this molecule and the role of mutations in its altered function offer new insights into a range of conditions not previously thought to be related to one another.
Abstract: Mutations in the filaggrin gene are associated with a broad range of skin and allergic diseases. The biology of this molecule and the role of mutations in its altered function offer new insights into a range of conditions not previously thought to be related to one another.
TL;DR: The findings suggest that dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis, and a common polymorphism in the promoter of M UC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrot.
Abstract: A b s t r ac t Background The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk Methods Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 34-Mb region of chromosome 11p15 in 82 families We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls MUC5B expression was assessed in lung tissue Results Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P = 12×10 − 15 ; allelic association with idiopathic pulmonary fibrosis, P = 25×10 − 37 ) The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 68 (95% confidence interval [CI], 39 to 120) and 208 (95% CI, 38 to 1137), respectively, for familial interstitial pneumonia and 90 (95% CI, 62 to 131) and 218 (95% CI, 51 to 935), respectively, for idiopathic pulmonary fibrosis MUC5B expression in the lung was 141 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P<0001) The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 374 times as high as in unaffected subjects homozygous for the wild-type allele, P<0001) MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis Conclusions A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis Our findings suggest that dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis (Funded by the National Heart, Lung, and Blood Institute and others)
Harvard University1, Stanford University2, University of Washington3, University of Florida4, Boston University5, University of Colorado Denver6, University of Texas Southwestern Medical Center7, University of Rochester8, University of Pittsburgh9, University of Toronto10, University of California, San Francisco11, Washington University in St. Louis12, University of Texas Medical Branch13, Loyola University Chicago14, Rutgers University15, Princeton University16
TL;DR: It is shown that critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes that alter the status of these genes in the immune system.
Abstract: Human survival from injury requires an appropriate inflammatory and immune response. We describe the circulating leukocyte transcriptome after severe trauma and burn injury, as well as in healthy subjects receiving low-dose bacterial endotoxin, and show that these severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected “genomic storm.” In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously increased expression of genes involved in the systemic inflammatory, innate immune, and compensatory antiinflammatory responses, as well as in the suppression of genes involved in adaptive immunity. Furthermore, complications like nosocomial infections and organ failure are not associated with any genomic evidence of a second hit and differ only in the magnitude and duration of this genomic reprioritization. The similarities in gene expression patterns between different injuries reveal an apparently fundamental human response to severe inflammatory stress, with genomic signatures that are surprisingly far more common than different. Based on these transcriptional data, we propose a new paradigm for the human immunological response to severe injury.
TL;DR: In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life.
Abstract: In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683.)
TL;DR: New insights into the genetics and pathophysiology of AD point to an important role of structural abnormalities in the epidermis as well as immune dysregulation not only for this skin disease but also for the development of asthma and allergies.
Abstract: Atopic dermatitis (AD) is an important chronic or relapsing inflammatory skin disease that often precedes asthma and allergic disorders. New insights into the genetics and pathophysiology of AD point to an important role of structural abnormalities in the epidermis as well as immune dysregulation not only for this skin disease but also for the development of asthma and allergies. Patients with AD have a unique predisposition to colonization or infection by microbial organisms, most notably Staphylococcus aureus and herpes simplex virus. Measures directed at healing and protecting the skin barrier and addressing the immune dysregulation are essential in the treatment of patients with AD, and early intervention may improve outcomes for both the skin disease as well as other target organs.
University of Cincinnati1, National Institutes of Health2, University of Toronto3, Medical University of South Carolina4, Niigata University5, Oregon Health & Science University6, Cleveland Clinic7, University of Florida8, University of Texas Health Science Center at Tyler9, University of Colorado Denver10, University of California, Los Angeles11, Harvard University12, Cincinnati Children's Hospital Medical Center13, Mayo Clinic14, University of South Florida15
TL;DR: In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life.
Abstract: Background Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1–2 trials involving patients with LAM. Methods We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment — a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV1). Results During the treatment period, the FEV1 slope was −12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV1 during the treatment period was 153 ml, o...
TL;DR: There is no effective pharmacologic therapy, although cell-based therapy and other therapies currently being tested in clinical trials may provide novel treatments for ARDS.
Abstract: The acute respiratory distress syndrome (ARDS) causes 40% mortality in approximately 200,000 critically ill patients annually in the United States. ARDS is caused by protein-rich pulmonary edema that causes severe hypoxemia and impaired carbon dioxide excretion. The clinical disorders associated with the development of ARDS include sepsis, pneumonia, aspiration of gastric contents, and major trauma. The lung injury is caused primarily by neutrophil-dependent and platelet-dependent damage to the endothelial and epithelial barriers of the lung. Resolution is delayed because of injury to the lung epithelial barrier, which prevents removal of alveolar edema fluid and deprives the lung of adequate quantities of surfactant. Lymphocytes may play a role in resolution of lung injury. Mortality has been markedly reduced with a lung-protective ventilatory strategy. However, there is no effective pharmacologic therapy, although cell-based therapy and other therapies currently being tested in clinical trials may provi...
Public Health Foundation of India1, University of Edinburgh2, International Centre for Diarrhoeal Disease Research, Bangladesh3, Centers for Disease Control and Prevention4, University of Barcelona5, University of Oxford6, University of the Witwatersrand7, University of California, Berkeley8, National Institutes of Health9, Fukushima Medical University10, Medical Research Council11, All India Institute of Medical Sciences12, University of Colorado Denver13, Research Institute for Tropical Medicine14, Kenya Medical Research Institute15, Johns Hopkins University16, Pasteur Institute17, Delta State University18, University of Pretoria19, Columbia University20, World Health Organization21, Emory University22, Dartmouth College23, University of Split24
TL;DR: The role of influenza in childhood mortality from ALRI is estimated by combining incidence estimates with case fatality ratios from hospital-based reports and identifying studies with population-based data for influenza seasonality and monthly ALRI mortality.
Emory University1, University of Alabama at Birmingham2, University of Louisville3, St. Luke's Hospital4, Kaiser Permanente5, Mount Sinai St. Luke's and Mount Sinai Roosevelt6, Mayo Clinic7, Ohio State University8, Carolinas Medical Center9, University of Colorado Denver10, Northwestern University11, Advocate Lutheran General Hospital12, University of South Florida13, Rush University Medical Center14, National Institutes of Health15, University of Texas MD Anderson Cancer Center16
TL;DR: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine andInterleukin-2 than with interleuk in-2 alone.
Abstract: Background Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. Methods We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end p...
TL;DR: To define precisely what MTurk is and what it is not, it is hoped that this will point out opportunities for the community to deliberately value ethics above cost savings.
Abstract: Recently heard at a tutorial in our field: “It cost me less than one hundred bucks to annotate this using Amazon Mechanical Turk!” Assertions like this are increasingly common, but we believe they should not be stated so proudly; they ignore the ethical consequences of using MTurk (Amazon Mechanical Turk) as a source of labor. Manually annotating corpora or manually developing any other linguistic resource, such as a set of judgments about system outputs, represents such a high cost that many researchers are looking for alternative solutions to the standard approach. MTurk is becoming a popular one. However, as in any scientific endeavor involving humans, there is an unspoken ethical dimension involved in resource construction and system evaluation, and this is especially true of MTurk. We would like here to raise some questions about the use of MTurk. To do so, we will define precisely what MTurk is and what it is not, highlighting the issues raised by the system. We hope that this will point out opportunities for our community to deliberately value ethics above cost savings.
University of Cincinnati1, Northwestern University2, Harvard University3, University of Florida4, Johns Hopkins University5, University of Colorado Denver6, University of North Carolina at Chapel Hill7, Université libre de Bruxelles8, University of Amsterdam9, Vertex Pharmaceuticals10, Cedars-Sinai Medical Center11
TL;DR: Among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients.
Abstract: We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon– ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48. Results Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, −2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001). Conclusions In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon–ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.)
TL;DR: The dysregulation of Nrf2-regulated genes provides a logical explanation for the connections between observable oxidative stress and perhaps 200 human diseases involving these various physiological processes, each reflecting a network involving many gene products.
TL;DR: When added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma.
Abstract: Among 419 participants who underwent randomization (at which point 73% had moderate or severe disease), omalizumab as compared with placebo significantly reduced the number of days with asthma symptoms, from 1.96 to 1.48 days per 2-week interval, a 24.5% decrease (P<0.001). Similarly, omalizumab significantly reduced the proportion of participants who had one or more exacerbations from 48.8 to 30.3% (P<0.001). Improvements occurred with omalizumab despite reductions in the use of inhaled glucocorticoids and long-acting beta-agonists. Conclusions When added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma. (Funded by the National Institute of Allergy and Infectious Diseases and Novartis; ClinicalTrials.gov number, NCT00377572.)
TL;DR: It is reported that dying tumor cells use the apoptotic process to generate potent growth-stimulating signals to stimulate the repopulation of tumors undergoing radiotherapy, and activated caspase 3, a key executioner in apoptosis, is involved in the growth stimulation.
Abstract: In cancer treatment, apoptosis is a well-recognized cell death mechanism through which cytotoxic agents kill tumor cells. Here we report that dying tumor cells use the apoptotic process to generate potent growth-stimulating signals to stimulate the repopulation of tumors undergoing radiotherapy. Furthermore, activated caspase 3, a key executioner in apoptosis, is involved in the growth stimulation. One downstream effector that caspase 3 regulates is prostaglandin E(2) (PGE(2)), which can potently stimulate growth of surviving tumor cells. Deficiency of caspase 3 either in tumor cells or in tumor stroma caused substantial tumor sensitivity to radiotherapy in xenograft or mouse tumors. In human subjects with cancer, higher amounts of activated caspase 3 in tumor tissues are correlated with markedly increased rate of recurrence and death. We propose the existence of a cell death-induced tumor repopulation pathway in which caspase 3 has a major role.
TL;DR: This paper used meta-analytic techniques to examine the instructional effectiveness of computer-based simulation games relative to a comparison group (k= 65, N= 6,476) and found that trainees learned less from simulation games than comparison instructional methods when the instruction the comparison group received as a substitute for the simulation game actively engaged them in the learning experience.
Abstract: Interactive cognitive complexity theory suggests that simulation games are more effective than other instructional methods because they simultaneously engage trainees’ affective and cognitive processes (Tennyson & Jorczak, 2008). Meta-analytic techniques were used to examine the instructional effectiveness of computer-based simulation games relative to a comparison group (k= 65, N= 6,476). Consistent with theory, posttraining self-efficacy was 20% higher, declarative knowledge was 11% higher, procedural knowledge was 14% higher, and retention was 9% higher for trainees taught with simulation games, relative to a comparison group. However, the results provide strong evidence of publication bias in simulation games research. Characteristics of simulation games and the instructional context also moderated the effectiveness of simulation games. Trainees learned more, relative to a comparison group, when simulation games conveyed course material actively rather than passively, trainees could access the simulation game as many times as desired, and the simulation game was a supplement to other instructional methods rather than stand-alone instruction. However, trainees learned less from simulation games than comparison instructional methods when the instruction the comparison group received as a substitute for the simulation game actively engaged them in the learning experience.
TL;DR: Evidence for the involvement of IL‐1β and the clinical results of reducing IL‐ 1β activity in this broad spectrum of inflammatory diseases are the focus of this review.
Abstract: An expanding spectrum of acute and chronic non-infectious inflammatory diseases is uniquely responsive to IL-1β neutralization. IL-1β-mediated diseases are often called "auto-inflammatory" and the dominant finding is the release of the active form of IL-1β driven by endogenous molecules acting on the monocyte/macrophage. IL-1β activity is tightly controlled and requires the conversion of the primary transcript, the inactive IL-1β precursor, to the active cytokine by limited proteolysis. Limited proteolysis can take place extracellularly by serine proteases, released in particular by infiltrating neutrophils or intracellularly by the cysteine protease caspase-1. Therefore, blocking IL-1β resolves inflammation regardless of how the cytokine is released from the cell or how the precursor is cleaved. Endogenous stimulants such as oxidized fatty acids and lipoproteins, high glucose concentrations, uric acid crystals, activated complement, contents of necrotic cells, and cytokines, particularly IL-1 itself, induce the synthesis of the inactive IL-1β precursor, which awaits processing to the active form. Although bursts of IL-1β precipitate acute attacks of systemic or local inflammation, IL-1β also contributes to several chronic diseases. For example, ischemic injury, such as myocardial infarction or stroke, causes acute and extensive damage, and slowly progressive inflammatory processes take place in atherosclerosis, type 2 diabetes, osteoarthritis and smoldering myeloma. Evidence for the involvement of IL-1β and the clinical results of reducing IL-1β activity in this broad spectrum of inflammatory diseases are the focus of this review.
TL;DR: Elevated urine IL-18 and urine NGAL levels associated with longer hospital stay, longer intensive care unit stay, and duration of mechanical ventilation, but not plasma NGAL, associate with subsequent AKI and poor outcomes among children undergoing cardiac surgery.
Abstract: Acute kidney injury (AKI) occurs commonly after pediatric cardiac surgery and associates with poor outcomes. Biomarkers may help the prediction or early identification of AKI, potentially increasing opportunities for therapeutic interventions. Here, we conducted a prospective, multicenter cohort study involving 311 children undergoing surgery for congenital cardiac lesions to evaluate whether early postoperative measures of urine IL-18, urine neutrophil gelatinase-associated lipocalin (NGAL), or plasma NGAL could identify which patients would develop AKI and other adverse outcomes. Urine IL-18 and urine and plasma NGAL levels peaked within 6 hours after surgery. Severe AKI, defined by dialysis or doubling in serum creatinine during hospital stay, occurred in 53 participants at a median of 2 days after surgery. The first postoperative urine IL-18 and urine NGAL levels strongly associated with severe AKI. After multivariable adjustment, the highest quintiles of urine IL-18 and urine NGAL associated with 6.9- and 4.1-fold higher odds of AKI, respectively, compared with the lowest quintiles. Elevated urine IL-18 and urine NGAL levels associated with longer hospital stay, longer intensive care unit stay, and duration of mechanical ventilation. The accuracy of urine IL-18 and urine NGAL for diagnosis of severe AKI was moderate, with areas under the curve of 0.72 and 0.71, respectively. The addition of these urine biomarkers improved risk prediction over clinical models alone as measured by net reclassification improvement and integrated discrimination improvement. In conclusion, urine IL-18 and urine NGAL, but not plasma NGAL, associate with subsequent AKI and poor outcomes among children undergoing cardiac surgery.
TL;DR: The results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.
Abstract: Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.