Showing papers by "Harvard University published in 2003"
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TL;DR: This paper developed a dynamic industry model with heterogeneous firms to analyze the intra-industry effects of international trade and showed how the exposure to trade will induce only the more productive firms to enter the export market (while some less productive firms continue to produce only for the domestic market).
Abstract: This paper develops a dynamic industry model with heterogeneous firms to analyze the intra-industry effects of international trade. The model shows how the exposure to trade will induce only the more productive firms to enter the export market (while some less productive firms continue to produce only for the domestic market) and will simultaneously force the least productive firms to exit. It then shows how further increases in the industry's exposure to trade lead to additional inter-firm reallocations towards more productive firms. The paper also shows how the aggregate industry productivity growth generated by the reallocations contributes to a welfare gain, thus highlighting a benefit from trade that has not been examined theoretically before. The paper adapts Hopenhayn's (1992a) dynamic industry model to monopolistic competition in a general equilibrium setting. In so doing, the paper provides an extension of Krugman's (1980) trade model that incorporates firm level productivity differences. Firms with different productivity levels coexist in an industry because each firm faces initial uncertainty concerning its productivity before making an irreversible investment to enter the industry. Entry into the export market is also costly, but the firm's decision to export occurs after it gains knowledge of its productivity.
9,036 citations
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01 Jan 2003TL;DR: In this paper, a framework for investigating change over time is presented, where the multilevel model for change is introduced and a framework is presented for investigating event occurrence over time.
Abstract: PART I 1. A framework for investigating change over time 2. Exploring Longitudinal Data on Change 3. Introducing the multilevel model for change 4. Doing data analysis with the multilevel mode for change 5. Treating TIME more flexibly 6. Modelling discontinuous and nonlinear change 7. Examining the multilevel model's error covariance structure 8. Modelling change using covariance structure analysis PART II 9. A Framework for Investigating Event Occurrence 10. Describing discrete-time event occurrence data 11. Fitting basic Discrete-Time Hazard Models 12. Extending the Discrete-Time Hazard Model 13. Describing Continuous-Time Event Occurrence Data 14. Fitting Cox Regression Models 15. Extending the Cox Regression Model
8,435 citations
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TL;DR: An analytical strategy is introduced, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes, which identifies a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle.
Abstract: DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.
7,997 citations
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TL;DR: Notably, major depressive disorder is a common disorder, widely distributed in the population, and usually associated with substantial symptom severity and role impairment, and while the recent increase in treatment is encouraging, inadequate treatment is a serious concern.
Abstract: ContextUncertainties exist about prevalence and correlates of major depressive
disorder (MDD).ObjectiveTo present nationally representative data on prevalence and correlates
of MDD by Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition (DSM-IV) criteria, and on study
patterns and correlates of treatment and treatment adequacy from the recently
completed National Comorbidity Survey Replication (NCS-R).DesignFace-to-face household survey conducted from February 2001 to December
2002.SettingThe 48 contiguous United States.ParticipantsHousehold residents ages 18 years or older (N = 9090) who responded
to the NCS-R survey.Main Outcome MeasuresPrevalence and correlates of MDD using the World Health Organization's
(WHO) Composite International Diagnostic Interview (CIDI), 12-month severity
with the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR),
the Sheehan Disability Scale (SDS), and the WHO disability assessment scale
(WHO-DAS). Clinical reinterviews used the Structured Clinical Interview for DSM-IV.ResultsThe prevalence of CIDI MDD for lifetime was 16.2% (95% confidence interval
[CI], 15.1-17.3) (32.6-35.1 million US adults) and for 12-month was 6.6% (95%
CI, 5.9-7.3) (13.1-14.2 million US adults). Virtually all CIDI 12-month cases
were independently classified as clinically significant using the QIDS-SR,
with 10.4% mild, 38.6% moderate, 38.0% severe, and 12.9% very severe. Mean
episode duration was 16 weeks (95% CI, 15.1-17.3). Role impairment as measured
by SDS was substantial as indicated by 59.3% of 12-month cases with severe
or very severe role impairment. Most lifetime (72.1%) and 12-month (78.5%)
cases had comorbid CIDI/DSM-IV disorders, with MDD
only rarely primary. Although 51.6% (95% CI, 46.1-57.2) of 12-month cases
received health care treatment for MDD, treatment was adequate in only 41.9%
(95% CI, 35.9-47.9) of these cases, resulting in 21.7% (95% CI, 18.1-25.2)
of 12-month MDD being adequately treated. Sociodemographic correlates of treatment
were far less numerous than those of prevalence.ConclusionsMajor depressive disorder is a common disorder, widely distributed in
the population, and usually associated with substantial symptom severity and
role impairment. While the recent increase in treatment is encouraging, inadequate
treatment is a serious concern. Emphasis on screening and expansion of treatment
needs to be accompanied by a parallel emphasis on treatment quality improvement.
7,706 citations
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Baylor College of Medicine1, Chinese Academy of Sciences2, Chinese National Human Genome Center3, University of Hong Kong4, The Chinese University of Hong Kong5, Hong Kong University of Science and Technology6, Illumina7, McGill University8, Washington University in St. Louis9, University of California, San Francisco10, Wellcome Trust Sanger Institute11, Beijing Normal University12, Health Sciences University of Hokkaido13, Shinshu University14, University of Tsukuba15, Howard University16, University of Ibadan17, Case Western Reserve University18, University of Utah19, Cold Spring Harbor Laboratory20, Johns Hopkins University21, University of Oxford22, North Carolina State University23, National Institutes of Health24, Massachusetts Institute of Technology25, Chinese Academy of Social Sciences26, Kyoto University27, Nagasaki University28, Wellcome Trust29, Genome Canada30, Foundation for the National Institutes of Health31, University of Maryland, Baltimore32, Vanderbilt University33, Stanford University34, University of California, Berkeley35, New York University36, University of Oklahoma37, University of New Mexico38, Université de Montréal39, University of California, Los Angeles40, University of Michigan41, University of Wisconsin-Madison42, London School of Economics and Political Science43, Genetic Alliance44, GlaxoSmithKline45, University of Washington46, Harvard University47, University of Chicago48, Fred Hutchinson Cancer Research Center49, University of Tokyo50
TL;DR: The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance the ability to choose targets for therapeutic intervention.
Abstract: The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.
5,926 citations
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TL;DR: It is found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells, indicating that ACE2 is a functional receptor for SARS-CoV.
Abstract: Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells Together our data indicate that ACE2 is a functional receptor for SARS-CoV
5,149 citations
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TL;DR: The best-performing measure incorporates data from the IAT's practice trials, uses a metric that is calibrated by each respondent's latency variability, and includes a latency penalty for errors, and strongly outperforms the earlier (conventional) procedure.
Abstract: In reporting Implicit Association Test (IAT) results, researchers have most often used scoring conventions described in the first publication of the IAT (A.G. Greenwald, D.E. McGhee, & J.L.K. Schwartz, 1998). Demonstration IATs available on the Internet have produced large data sets that were used in the current article to evaluate alternative scoring procedures. Candidate new algorithms were examined in terms of their (a) correlations with parallel self-report measures, (b) resistance to an artifact associated with speed of responding, (c) internal consistency, (d) sensitivity to known influences on IAT measures, and (e) resistance to known procedural influences. The best-performing measure incorporates data from the IAT's practice trials, uses a metric that is calibrated by each respondent's latency variability, and includes a latency penalty for errors. This new algorithm strongly outperforms the earlier (conventional) procedure.
5,049 citations
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TL;DR: PDT is being tested in the clinic for use in oncology — to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin.
Abstract: The therapeutic properties of light have been known for thousands of years, but it was only in the last century that photodynamic therapy (PDT) was developed. At present, PDT is being tested in the clinic for use in oncology--to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin. How does PDT work, and how can it be used to treat cancer and other diseases?
5,041 citations
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TL;DR: The authors argue that companies are increasingly asked to provide innovative solutions to deep-seated problems of human misery, even as economic theory instructs managers to focus on maximizing their shareholders' wealt.
Abstract: Companies are increasingly asked to provide innovative solutions to deep-seated problems of human misery, even as economic theory instructs managers to focus on maximizing their shareholders' wealt
4,666 citations
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TL;DR: In this randomized clinical trial involving patients with complex coronary lesions, the use of a sirolimus-eluting stent had a consistent treatment effect, reducing the rates of restenosis and associated clinical events in all subgroups analyzed.
Abstract: Background Preliminary reports of studies involving simple coronary lesions indicate that a sirolimus-eluting stent significantly reduces the risk of restenosis after percutaneous coronary revascularization. Methods We conducted a randomized, double-blind trial comparing a sirolimus-eluting stent with a standard stent in 1058 patients at 53 centers in the United States who had a newly diagnosed lesion in a native coronary artery. The coronary disease in these patients was complex because of the frequent presence of diabetes (in 26 percent of patients), the high percentage of patients with longer lesions (mean, 14.4 mm), and small vessels (mean, 2.80 mm). The primary end point was failure of the target vessel (a composite of death from cardiac causes, myocardial infarction, and repeated percutaneous or surgical revascularization of the target vessel) within 270 days. Results The rate of failure of the target vessel was reduced from 21.0 percent with a standard stent to 8.6 percent with a sirolimus-eluting ...
4,271 citations
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TL;DR: The brevity and accuracy of the K6 and K10 scales make them attractive screens for SMI, and routine inclusion of either scale in clinical studies would create an important, and heretofore missing, crosswalk between community and clinical epidemiology.
Abstract: Background Public Law 102-321 established a block grant for adults with "serious mental illness" (SMI) and required the Substance Abuse and Mental Health Services Administration (SAMHSA) to develop a method to estimate the prevalence of SMI. Methods Three SMI screening scales were developed for possible use in the SAMHSA National Household Survey on Drug Abuse: the Composite International Diagnostic Interview Short-Form (CIDI-SF) scale, the K10/K6 nonspecific distress scales, and the World Health Organization Disability Assessment Schedule (WHO-DAS). An enriched convenience sample of 155 respondents was administered all screening scales followed by the 12-month Structured Clinical Interview for DSM-IV and the Global Assessment of Functioning (GAF). We defined SMI as any 12-month DSM-IV disorder, other than a substance use disorder, with a GAF score of less than 60. Results All screening scales were significantly related to SMI. However, neither the CIDI-SF nor the WHO-DAS improved prediction significantly over the K10 or K6 scales. The area under the receiver operating characteristic curve of SMI was 0.854 for K10 and 0.865 for K6. The most efficient screening scale, K6, had a sensitivity (SE) of 0.36 (0.08) and a specificity of 0.96 (0.02) in predicting SMI. Conclusions The brevity and accuracy of the K6 and K10 scales make them attractive screens for SMI. Routine inclusion of either scale in clinical studies would create an important, and heretofore missing, crosswalk between community and clinical epidemiology.
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TL;DR: In this article, a contingency view of process management's influence on both technological innovation and organizational adaptation is developed, arguing that while process management activities are beneficial for organizations in stable contexts, they are fundamentally inconsistent with all but incremental innovation and change.
Abstract: We develop a contingency view of process management's influence on both technological innovation and organizational adaptation. We argue that while process management activities are beneficial for organizations in stable contexts, they are fundamentally inconsistent with all but incremental innovation and change. But dynamic capabilities are rooted in both exploitative and exploratory activities. We argue that process management activities must be buffered from exploratory activities and that ambidextrous organizational forms provide the complex contexts for these inconsistent activities to coexist.
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TL;DR: A vulnerability framework for the assessment of coupled human–environment systems is presented and it is shown that vulnerability is registered not by exposure to hazards alone but also resides in the sensitivity and resilience of the system experiencing such hazards.
Abstract: Global environmental change and sustainability science increasingly recognize the need to address the consequences of changes taking place in the structure and function of the biosphere. These changes raise questions such as: Who and what are vulnerable to the multiple environmental changes underway, and where? Research demonstrates that vulnerability is registered not by exposure to hazards (perturbations and stresses) alone but also resides in the sensitivity and resilience of the system experiencing such hazards. This recognition requires revisions and enlargements in the basic design of vulnerability assessments, including the capacity to treat coupled human–environment systems and those linkages within and without the systems that affect their vulnerability. A vulnerability framework for the assessment of coupled human–environment systems is presented.
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TL;DR: Since the major defect leading to a decrease in β-cell mass in type 2 diabetes is increased apoptosis, while new islet formation andβ-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 Diabetes.
Abstract: Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in beta-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m(2); 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m(2); 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative beta-cell volume, frequency of beta-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative beta-cell volume was increased in obese versus lean nondiabetic cases (P = 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative beta-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of beta-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of beta-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that beta-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased beta-cell apoptosis. Since the major defect leading to a decrease in beta-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and beta-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.
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TL;DR: It is confirmed that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt 1 that fall after delivery, and observations suggest that excess circulating sFelt1 contributes to the pathogenesis of preeClampsia.
Abstract: Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.
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TL;DR: The potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD+, and increases cell survival by stimulating Sirt1-dependent deacetylation of p53.
Abstract: In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.
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French Institute of Health and Medical Research1, Hospital Research Foundation2, University of Freiburg3, Medical Research Council4, Utrecht University5, Harvard University6, Pasteur Institute7, Babraham Institute8, University of Paris9, Curie Institute10, National Institutes of Health11, University of Sydney12, Ludwig Maximilian University of Munich13, LSU Health Sciences Center New Orleans14
TL;DR: Retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.
Abstract: We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.
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University of Washington1, University of Rochester2, AstraZeneca3, University of Queensland4, Pfizer5, Tufts University6, University of Pennsylvania7, Endo International plc8, University Health Network9, Harvard University10, Purdue Pharma11, Novartis12, National Institutes of Health13, Dalhousie University14, GlaxoSmithKline15, Food and Drug Administration16, Élan17, Abbott Laboratories18, University of California, San Diego19, United States Department of Veterans Affairs20
TL;DR: In this article, the authors provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain, and develop a core set of outcome domains would facilitate comparison and pooling of d
Abstract: Objective. To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of d
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TL;DR: Osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation.
Abstract: Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals. To explore the possibility that haematopoietic stem cells derive regulatory information from bone, accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs). Here we show that PPR-stimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, ligand-dependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by gamma-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.
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TL;DR: The authors showed that the large shocks that capital owners experienced during the Great Depression and World War II have had a permanent effect on top capital incomes and argued that steep progressive income and estate taxation may have prevented large fortunes from fully recovering from these shocks.
Abstract: This paper presents new homogeneous series on top shares of income and wages from 1913 to 1998 in the United States using individual tax returns data. Top income and wages shares display a U-shaped pattern over the century. Our series suggest that the large shocks that capital owners experienced during the Great Depression and World War II have had a permanent effect on top capital incomes. We argue that steep progressive income and estate taxation may have prevented large fortunes from fully recovering from these shocks. Top wage shares were flat before World War II, dropped precipitously during the war, and did not start to recover before the late 1960s but are now higher than before World War II. As a result, the working rich have replaced the rentiers at the top of the income distribution.
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TL;DR: In this paper, the authors investigated the economic effects of conflict, using the terrorist conflict in the Basque Country as a case study, and found that after the outbreak of terrorism in the late 1960's, per capita GDP in the basque country declined about 10 percentage points relative to a synthetic control region without terrorism.
Abstract: This article investigates the economic effects of conflict, using the terrorist conflict in the Basque Country as a case study. We find that, after the outbreak of terrorism in the late 1960's, per capita GDP in the Basque Country declined about 10 percentage points relative to a synthetic control region without terrorism. In addition, we use the 1998-1999 truce as a natural experiment. We find that stocks of firms with a significant part of their business in the Basque Country showed a positive relative performance when truce became credible, and a negative relative performance at the end of the cease-fire.
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TL;DR: This study suggests that efforts to mobilize S&T for sustainability are more likely to be effective when they manage boundaries between knowledge and action in ways that simultaneously enhance the salience, credibility, and legitimacy of the information they produce.
Abstract: The challenge of meeting human development needs while protecting the earth's life support systems confronts scientists, technologists, policy makers, and communities from local to global levels. Many believe that science and technology (S&T) must play a more central role in sustainable development, yet little systematic scholarship exists on how to create institutions that effectively harness S&T for sustainability. This study suggests that efforts to mobilize S&T for sustainability are more likely to be effective when they manage boundaries between knowledge and action in ways that simultaneously enhance the salience, credibility, and legitimacy of the information they produce. Effective systems apply a variety of institutional mechanisms that facilitate communication, translation and mediation across boundaries.
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TL;DR: A signaling pathway initiated by eIF2alpha phosphorylation protects cells against metabolic consequences of ER oxidation by promoting the linked processes of amino acid sufficiency and resistance to oxidative stress.
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Harvard University1, Aarhus University2, Memorial Hermann Texas Medical Center3, University of Texas at Austin4, National and Kapodistrian University of Athens5, University of Kentucky6, Utrecht University7, Icahn School of Medicine at Mount Sinai8, Tufts University9, Tulane University10, Armed Forces Institute of Pathology11, University of Washington12, Stanford University13, Erasmus University Rotterdam14, University of Turku15, University of Münster16, Mayo Clinic17, Emory University18, University of Bristol19, University of Ulm20, Veterans Health Administration21, University of Texas Health Science Center at Houston22, University of California, Los Angeles23, University of Pavia24, Pfizer25, University of Texas Southwestern Medical Center26, Lenox Hill Hospital27, Baylor College of Medicine28, University of Maryland, Baltimore29, Karolinska Institutet30, University of Chicago31, Cedars-Sinai Medical Center32, Northwestern University33, Indiana University34
TL;DR: The term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future and a quantitative method for cumulative risk assessment of vulnerable patients needs to be developed.
Abstract: Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.
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TL;DR: It is demonstrated that a short program in mindfulness meditation produces demonstrable effects on brain and immune function, and suggest that meditation may change brain andimmune function in positive ways and underscore the need for additional research.
Abstract: Objective:The underlying changes in biological processes that are associated with reported changes in mental and physical health in response to meditation have not been systematically explored. We performed a randomized, controlled study on the effects on brain and immune function of a well-known an
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Harvard University1, University of Arkansas at Little Rock2, Cedars-Sinai Medical Center3, Northwestern University4, Catholic Medical Center5, Mayo Clinic6, Cleveland Clinic7, University of South Florida8, University of Texas MD Anderson Cancer Center9, University of North Carolina at Chapel Hill10, Takeda Pharmaceutical Company11
TL;DR: Bortezomib, a member of a new class of anticancer drugs, is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy.
Abstract: Background Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been shown in preclinical and phase 1 studies to have antimyeloma activity. Methods In this multicenter, open-label, nonrandomized, phase 2 trial, we enrolled 202 patients with relapsed myeloma that was refractory to the therapy they had received most recently. Patients received 1.3 mg of bortezomib per square meter of body-surface area twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles (24 weeks). In patients with a suboptimal response, oral dexamethasone (20 mg daily, on the day of and the day after bortezomib administration) was added to the regimen. The response was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation and confirmed by an independent review committee. Results Of 193 patients who could be evaluated, 92 percent had been treated with three or more of the major classes of agents for myeloma, and in 91 percent, the myeloma wa...
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TL;DR: The past few years have seen an enormous increase in understanding of the signalling pathways and the transcription factors that control endochondral bone development.
Abstract: Vertebrates do not look like jellyfish because the bones of their skeletons are levers that allow movement and protect vital organs. Bones come in an enormous variety of shapes and sizes to accomplish these goals, but, with few exceptions, use one process--endochondral bone formation--to generate the skeleton. The past few years have seen an enormous increase in understanding of the signalling pathways and the transcription factors that control endochondral bone development.
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TL;DR: The maturation of nascent vasculature, formed by vasculogenesis or angiogenesis, requires recruitment of mural cells, generation of an extracellular matrix and specialization of the vessel wall for structural support and regulation of vessel function.
Abstract: The maturation of nascent vasculature, formed by vasculogenesis or angiogenesis, requires recruitment of mural cells, generation of an extracellular matrix and specialization of the vessel wall for structural support and regulation of vessel function. In addition, the vascular network must be organized so that all the parenchymal cells receive adequate nutrients. All of these processes are orchestrated by physical forces as well as by a constellation of ligands and receptors whose spatio-temporal patterns of expression and concentration are tightly regulated. Inappropriate levels of these physical forces or molecules produce an abnormal vasculature--a hallmark of various pathologies. Normalization of the abnormal vasculature can facilitate drug delivery to tumors and formation of a mature vasculature can help realize the promise of therapeutic angiogenesis and tissue engineering.
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TL;DR: It is found that solid tumors carrying the gene-expression signature were most likely to be associated with metastasis and poor clinical outcome, suggesting that the metastatic potential of human tumors is encoded in the bulk of aPrimary tumor, thus challenging the notion that metastases arise from rare cells within a primary tumor that have the ability to metastasize.
Abstract: Metastasis is the principal event leading to death in individuals with cancer, yet its molecular basis is poorly understood. To explore the molecular differences between human primary tumors and metastases, we compared the gene-expression profiles of adenocarcinoma metastases of multiple tumor types to unmatched primary adenocarcinomas. We found a gene-expression signature that distinguished primary from metastatic adenocarcinomas. More notably, we found that a subset of primary tumors resembled metastatic tumors with respect to this gene-expression signature. We confirmed this finding by applying the expression signature to data on 279 primary solid tumors of diverse types. We found that solid tumors carrying the gene-expression signature were most likely to be associated with metastasis and poor clinical outcome (P < 0.03). These results suggest that the metastatic potential of human tumors is encoded in the bulk of a primary tumor, thus challenging the notion that metastases arise from rare cells within a primary tumor that have the ability to metastasize.
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Cornell University1, Cedars-Sinai Medical Center2, University of Texas MD Anderson Cancer Center3, Harvard University4, University of California, Los Angeles5, University of Pittsburgh6, University of Wisconsin-Madison7, Anschutz Medical Campus8, Vanderbilt University9, Loyola University Chicago10, Northwestern University11, AstraZeneca12
TL;DR: Gefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved disease-related symptoms and induced radiographic tumor regressions in patients with NSCLC persisting after chemotherapy.
Abstract: ContextMore persons in the United States die from non–small cell lung
cancer (NSCLC) than from breast, colorectal, and prostate cancer combined.
In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors
that express the epidermal growth factor receptor (EGFR), a mediator of cell
signaling, and phase 1 trials have demonstrated that a fraction of patients
with NSCLC progressing after chemotherapy experience both a decrease in lung
cancer symptoms and radiographic tumor shrinkages with gefitinib.ObjectiveTo assess differences in symptomatic and radiographic response among
patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib.Design, Setting, and PatientsDouble-blind, randomized phase 2 trial conducted from November 2000
to April 2001 in 30 US academic and community oncology centers. Patients (N
= 221) had either stage IIIB or IV NSCLC for which they had received at least
2 chemotherapy regimens.InterventionDaily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib
tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching
placebo).Main Outcome MeasuresImprovement of NSCLC symptoms (2-point or greater increase in score
on the summed lung cancer subscale of the Functional Assessment of Cancer
Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion
size on imaging studies).ResultsOf 221 patients enrolled, 216 received gefitinib as randomized. Symptoms
of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients
receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving
500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial
radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving
250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg.
Symptoms improved in 96% of patients with partial radiographic responses.
The overall survival at 1 year was 25%. There were no significant differences
between the 250-mg and 500-mg doses in rates of symptom improvement (P = .26), radiographic tumor regression (P = .51), and projected 1-year survival (P =
.54). The 500-mg dose was associated more frequently with transient acne-like
rash (P = .04) and diarrhea (P = .006).ConclusionsGefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved
disease-related symptoms and induced radiographic tumor regressions in patients
with NSCLC persisting after chemotherapy.