Showing papers by "Emory University published in 2006"
TL;DR: In this article, the authors analyzed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8T cells.
Abstract: Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the 'helpless' CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections.
3,567 citations
TL;DR: The graded relationship of the ACE score to 18 different outcomes in multiple domains theoretically parallels the cumulative exposure of the developing brain to the stress response with resulting impairment in multiple brain structures and functions.
Abstract: Childhood maltreatment has been linked to a variety of changes in brain structure and function and stress–responsive neurobiological systems. Epidemiological studies have documented the impact of childhood maltreatment on health and emotional well–being. After a brief review of the neurobiology of childhood trauma, we use the Adverse Childhood Experiences (ACE) Study as an epidemiological “case example” of the convergence between epidemiologic and neurobiological evidence of the effects of childhood trauma. The ACE Study included 17,337 adult HMO members and assessed 8 adverse childhood experiences (ACEs) including abuse, witnessing domestic violence, and serious household dysfunction. We used the number of ACEs (ACE score) as a measure of cumulative childhood stress and hypothesized a "doseresponse" relationship of the ACE score to 18 selected outcomes and to the total number of these outcomes (comorbidity). Based upon logistic regression analysis, the risk of every outcome in the affective, somatic, substance abuse, memory, sexual,and aggressionrelated domains increased in a graded fashion as the ACE score increased (P <0.001). The mean number of comorbid outcomes tripled across the range of the ACE score. The graded relationship of the ACE score to 18 different outcomes in multiple domains theoretically parallels the cumulative exposure of the developing brain to the stress response with resulting impairment in multiple brain structures and functions.
3,284 citations
TL;DR: These findings suggest that targeting proinflammatory cytokines and their signaling pathways might represent a novel strategy to treat depression.
2,608 citations
TL;DR: The data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function.
Abstract: Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.
2,525 citations
Ohio State University1, Fred Hutchinson Cancer Research Center2, University of Cincinnati3, University of Iowa4, University of California, Davis5, University of Alabama at Birmingham6, University of Arizona7, University of Washington8, Rush University Medical Center9, Wake Forest University10, University of Nevada, Reno11, University of Texas at San Antonio12, Kaiser Permanente13, University of Pittsburgh14, University of California, Los Angeles15, Stony Brook University16, Baylor College of Medicine17, University of North Carolina at Chapel Hill18, Wayne State University19, Howard University20, George Washington University21, University of California, Irvine22, University of Tennessee Health Science Center23, Medical College of Wisconsin24, University of California, San Diego25, Rutgers University26, University of Florida27, National Institutes of Health28, Harvard University29, University of Minnesota30, University of Massachusetts Boston31, University of Miami32, Emory University33, University of Wisconsin-Madison34, Stanford University35, Northwestern University36, University at Buffalo37, Brown University38, Yeshiva University39
TL;DR: Among healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones.
Abstract: Background The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal. Methods We recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers. Results Hip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with...
1,765 citations
TL;DR: A critical analysis of lesion and neuroimaging studies using three popular executive function measures in order to examine the validity of the executive function construct in terms of its relation to activation and damage to the frontal lobes reveals mixed evidence that does not support a one-to-one relationship between executive functions and frontal lobe activity.
Abstract: Currently, there is debate among scholars regarding how to operationalize and measure executive functions. These functions generally are referred to as “supervisory” cognitive processes because they involve higher level organization and execution of complex thoughts and behavior. Although conceptualizations vary regarding what mental processes actually constitute the “executive function” construct, there has been a historical linkage of these “higher-level” processes with the frontal lobes. In fact, many investigators have used the term “frontal functions” synonymously with “executive functions” despite evidence that contradicts this synonymous usage. The current review provides a critical analysis of lesion and neuroimaging studies using three popular executive function measures (Wisconsin Card Sorting Test, Phonemic Verbal Fluency, and Stroop Color Word Interference Test) in order to examine the validity of the executive function construct in terms of its relation to activation and damage to the frontal lobes. Empirical lesion data are examined via meta-analysis procedures along with formula derivatives. Results reveal mixed evidence that does not support a one-to-one relationship between executive functions and frontal lobe activity. The paper concludes with a discussion of the implications of construing the validity of these neuropsychological tests in anatomical, rather than cognitive and behavioral, terms.
1,759 citations
TL;DR: The Extremity Constraint Induced Therapy Evaluation (EXCITE) trial as mentioned in this paper showed that a 2-week program of constraint-induced movement therapy (CIMT) for patients more than 1 year after stroke who maintain some hand and wrist movement can improve upper extremity function that persists for at least 1 year.
Abstract: ContextSingle-site studies suggest that a 2-week program of constraint-induced movement therapy (CIMT) for patients more than 1 year after stroke who maintain some hand and wrist movement can improve upper extremity function that persists for at least 1 year.ObjectiveTo compare the effects of a 2-week multisite program of CIMT vs usual and customary care on improvement in upper extremity function among patients who had a first stroke within the previous 3 to 9 months.Design and SettingThe Extremity Constraint Induced Therapy Evaluation (EXCITE) trial, a prospective, single-blind, randomized, multisite clinical trial conducted at 7 US academic institutions between January 2001 and January 2003.ParticipantsTwo hundred twenty-two individuals with predominantly ischemic stroke.InterventionsParticipants were assigned to receive either CIMT (n = 106; wearing a restraining mitt on the less-affected hand while engaging in repetitive task practice and behavioral shaping with the hemiplegic hand) or usual and customary care (n = 116; ranging from no treatment after concluding formal rehabilitation to pharmacologic or physiotherapeutic interventions); patients were stratified by sex, prestroke dominant side, side of stroke, and level of paretic arm function.Main Outcome MeasuresThe Wolf Motor Function Test (WMFT), a measure of laboratory time and strength-based ability and quality of movement (functional ability), and the Motor Activity Log (MAL), a measure of how well and how often 30 common daily activities are performed.ResultsFrom baseline to 12 months, the CIMT group showed greater improvements than the control group in both the WMFT Performance Time (decrease in mean time from 19.3 seconds to 9.3 seconds [52% reduction] vs from 24.0 seconds to 17.7 seconds [26% reduction]; between-group difference, 34% [95% confidence interval {CI}, 12%-51%]; P<.001) and in the MAL Amount of Use (on a 0-5 scale, increase from 1.21 to 2.13 vs from 1.15 to 1.65; between-group difference, 0.43 [95% CI, 0.05-0.80]; P<.001) and MAL Quality of Movement (on a 0-5 scale, increase from 1.26 to 2.23 vs 1.18 to 1.66; between-group difference, 0.48 [95% CI, 0.13-0.84]; P<.001). The CIMT group achieved a decrease of 19.5 in self-perceived hand function difficulty (Stroke Impact Scale hand domain) vs a decrease of 10.1 for the control group (between-group difference, 9.42 [95% CI, 0.27-18.57]; P=.05).ConclusionAmong patients who had a stroke within the previous 3 to 9 months, CIMT produced statistically significant and clinically relevant improvements in arm motor function that persisted for at least 1 year.Trial Registrationclinicaltrials.gov Identifier: NCT00057018
1,662 citations
TL;DR: From a mechanistic standpoint, oxidative stress may be better defined as a disruption of redox signaling and control and adoption of such a definition could redirect research to identify key perturbations of red Oxidative stress-related disease processes and lead to new treatments for oxidative stressed disease processes.
Abstract: Oxidative stress is often defined as an imbalance of pro-oxidants and antioxidants, which can be quantified in humans as the redox state of plasma GSH/GSSG. Plasma GSH redox in humans becomes oxidized with age, in response to oxidative stress (chemotherapy, smoking), and in common diseases (type 2 diabetes, cardiovascular disease). However, data also show that redox of plasma GSH/GSSG is not equilibrated with the larger plasma cysteine/cystine (Cys/CySS) pool, indicating that the "balance" of pro-oxidants and antioxidants cannot be defined by a single entity. The major cellular thiol/disulfide systems, including GSH/GSSG, thioredoxin- 1 (-SH2/-SS-), and Cys/CySS, are not in redox equilibrium and respond differently to chemical toxicants and physiologic stimuli. Individual signaling and control events occur through discrete redox pathways rather than through mechanisms that are directly responsive to a global thiol/disulfide balance such as that conceptualized in the common definition of oxidative stress. ...
1,438 citations
Wayne State University1, George Washington University2, Medical College of Wisconsin3, Michigan State University4, Harvard University5, University of Calgary6, Emory University7, Henry Ford Health System8, Cornell University9, Houston Methodist Hospital10, Duke University11, University of Michigan12
TL;DR: In patients with suspected pulmonary embolism, multidetector CTA-CTV has a higher diagnostic sensitivity than does CTA alone, with similar specificity, and additional testing is necessary when the clinical probability is inconsistent with the imaging results.
Abstract: BACKGROUND The accuracy of multidetector computed tomographic angiography (CTA) for the diagnosis of acute pulmonary embolism has not been determined conclusively. METHODS The Prospective Investigation of Pulmonary Embolism Diagnosis II trial was a prospective, multicenter investigation of the accuracy of multidetector CTA alone and combined with venous-phase imaging (CTA-CTV) for the diagnosis of acute pulmonary embolism. We used a composite reference test to confirm or rule out the diagnosis of pulmonary embolism. RESULTS Among 824 patients with a reference diagnosis and a completed CT study, CTA was inconclusive in 51 because of poor image quality. Excluding such inconclusive studies, the sensitivity of CTA was 83 percent and the specificity was 96 percent. Positive predictive values were 96 percent with a concordantly high or low probability on clinical assessment, 92 percent with an intermediate probability on clinical assessment, and nondiagnostic if clinical probability was discordant. CTA-CTV was inconclusive in 87 of 824 patients because the image quality of either CTA or CTV was poor. The sensitivity of CTA-CTV for pulmonary embolism was 90 percent, and specificity was 95 percent. CTA-CTV was also nondiagnostic with a discordant clinical probability. CONCLUSIONS In patients with suspected pulmonary embolism, multidetector CTA-CTV has a higher diagnostic sensitivity than does CTA alone, with similar specificity. The predictive value of either CTA or CTA-CTV is high with a concordant clinical assessment, but additional testing is necessary when the clinical probability is inconsistent with the imaging results.
1,374 citations
Emory University1, University of California, Davis2, University of Oxford3, California Institute of Technology4, University of California, Los Angeles5, College of DuPage6, University of Los Andes7, University of California, Santa Barbara8, Guilford College9, Washington University in St. Louis10, Harvard University11, University of Colorado Denver12, Boise State University13
TL;DR: Experimental results from 15 diverse populations show that all populations demonstrate some willingness to administer costly punishment as unequal behavior increases, and the magnitude of this punishment varies substantially across populations, and costly punishment positively covaries with altruistic behavior across populations.
Abstract: Recent behavioral experiments aimed at understanding the evolutionary foundations of human cooperation have suggested that a willingness to engage in costly punishment, even in one-shot situations, may be part of human psychology and a key element in understanding our sociality. However, because most experiments have been confined to students in industrialized societies, generalizations of these insights to the species have necessarily been tentative. Here, experimental results from 15 diverse populations show that (i) all populations demonstrate some willingness to administer costly punishment as unequal behavior increases, (ii) the magnitude of this punishment varies substantially across populations, and (iii) costly punishment positively covaries with altruistic behavior across populations. These findings are consistent with models of the gene-culture coevolution of human altruism and further sharpen what any theory of human cooperation needs to explain.
1,334 citations
TL;DR: This paper articulates the understanding of how complex systems change and what determines their ability to absorb disturbances in either their ecological or their social domains and presents a list of some that could help define the next phase of resilience-related research.
Abstract: This paper is a work-in-progress account of ideas and propositions about resilience in socialecological systems. It articulates our understanding of how these complex systems change and what determines their ability to absorb disturbances in either their ecological or their social domains. We call them “propositions” because, although they are useful in helping us understand and compare different social-ecological systems, they are not sufficiently well defined to be considered formal hypotheses. These propositions were developed in two workshops, in 2003 and 2004, in which participants compared the dynamics of 15 case studies in a wide range of regions around the world. The propositions raise many questions, and we present a list of some that could help define the next phase of resilience-related research.
TL;DR: In this paper, the direct and interactive effects of relationship strength, network position, and external ties on individual creative contributions are explored, integrating creativity and social network theories, and the results show that relationship strength and network position affect individual creative contribution.
Abstract: Integrating creativity and social network theories, I explore the direct and interactive effects of relationship strength, network position, and external ties on individual creative contributions. ...
TL;DR: This work evaluates claims and some counter-claims made about the physiological importance of these enzymes and the potential of their inhibitors in the light of what the authors know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitor.
Abstract: Monoamine oxidase inhibitors were among the first antidepressants to be discovered and have long been used as such. It now seems that many of these agents might have therapeutic value in several common neurodegenerative conditions, independently of their inhibition of monoamine oxidase activity. However, many claims and some counter-claims have been made about the physiological importance of these enzymes and the potential of their inhibitors. We evaluate these arguments in the light of what we know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitors.
Colorado State University1, National Park Service2, University of Rhode Island3, United States Environmental Protection Agency4, Emory University5, University of Maryland, College Park6, University of North Carolina at Chapel Hill7, University of Wisconsin-Madison8, Duke University9, The Nature Conservancy10
TL;DR: The scope of the thresholds concept in ecological science is defined and methods for identifying and investigating thresholds using a variety of examples from terrestrial and aquatic environments, at ecosystem, landscape and regional scales are discussed.
Abstract: An ecological threshold is the point at which there is an abrupt change in an ecosystem quality, property or phenomenon, or where small changes in an environmental driver produce large responses in the ecosystem. Analysis of thresholds is complicated by nonlinear dynamics and by multiple factor controls that operate at diverse spatial and temporal scales. These complexities have challenged the use and utility of threshold concepts in environmental management despite great concern about preventing dramatic state changes in valued ecosystems, the need for determining critical pollutant loads and the ubiquity of other threshold-based environmental problems. In this paper we define the scope of the thresholds concept in ecological science and discuss methods for identifying and investigating thresholds using a variety of examples from terrestrial and aquatic environments, at ecosystem, landscape and regional scales. We end with a discussion of key research needs in this area.
Howard University1, Memorial Hospital of South Bend2, Northwestern University3, George Washington University4, Harvard University5, Stanford University6, Yeshiva University7, University of Pittsburgh8, Fred Hutchinson Cancer Research Center9, University of California, San Diego10, Rutgers University11, University of Alabama at Birmingham12, University of Florida13, University of Minnesota14, Ohio State University15, University of Massachusetts Medical School16, University of Miami17, Emory University18, University of California, Davis19, National Institutes of Health20, University of Wisconsin-Madison21, University of Iowa22, Kaiser Permanente23, University at Buffalo24, Wake Forest University25, Pfizer26, Brown University27, University of Arizona28, Rush University Medical Center29, University of Nevada, Reno30, University of Texas at San Antonio31, University of California, Los Angeles32, University of Cincinnati33, Stony Brook University34, Baylor College of Medicine35, University of North Carolina at Chapel Hill36, Wayne State University37, University of California, Irvine38, University of Tennessee Health Science Center39, Medical College of Wisconsin40
TL;DR: A dietary intervention that reduced total fat intake and increased intakes of vegetables, fruits, and grains did not significantly reduce the risk of CHD, stroke, or CVD in postmenopausal women and achieved only modest effects on CVD risk factors, suggesting that more focused diet and lifestyle interventions may be needed to improve risk factors and reduce CVDrisk.
Abstract: ContextMultiple epidemiologic studies and some trials have linked diet with cardiovascular disease (CVD) prevention, but long-term intervention data are needed.ObjectiveTo test the hypothesis that a dietary intervention, intended to be low in fat and high in vegetables, fruits, and grains to reduce cancer, would reduce CVD risk.Design, Setting, and ParticipantsRandomized controlled trial of 48 835 postmenopausal women aged 50 to 79 years, of diverse backgrounds and ethnicities, who participated in the Women's Health Initiative Dietary Modification Trial. Women were randomly assigned to an intervention (19 541 [40%]) or comparison group (29 294 [60%]) in a free-living setting. Study enrollment occurred between 1993 and 1998 in 40 US clinical centers; mean follow-up in this analysis was 8.1 years.InterventionIntensive behavior modification in group and individual sessions designed to reduce total fat intake to 20% of calories and increase intakes of vegetables/fruits to 5 servings/d and grains to at least 6 servings/d. The comparison group received diet-related education materials.Main Outcome MeasuresFatal and nonfatal coronary heart disease (CHD), fatal and nonfatal stroke, and CVD (composite of CHD and stroke).ResultsBy year 6, mean fat intake decreased by 8.2% of energy intake in the intervention vs the comparison group, with small decreases in saturated (2.9%), monounsaturated (3.3%), and polyunsaturated (1.5%) fat; increases occurred in intakes of vegetables/fruits (1.1 servings/d) and grains (0.5 serving/d). Low-density lipoprotein cholesterol levels, diastolic blood pressure, and factor VIIc levels were significantly reduced by 3.55 mg/dL, 0.31 mm Hg, and 4.29%, respectively; levels of high-density lipoprotein cholesterol, triglycerides, glucose, and insulin did not significantly differ in the intervention vs comparison groups. The numbers who developed CHD, stroke, and CVD (annualized incidence rates) were 1000 (0.63%), 434 (0.28%), and 1357 (0.86%) in the intervention and 1549 (0.65%), 642 (0.27%), and 2088 (0.88%) in the comparison group. The diet had no significant effects on incidence of CHD (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.90-1.06), stroke (HR, 1.02; 95% CI, 0.90-1.15), or CVD (HR, 0.98; 95% CI, 0.92-1.05). Excluding participants with baseline CVD (3.4%), the HRs (95% CIs) for CHD and stroke were 0.94 (0.86-1.02) and 1.02 (0.90-1.17), respectively. Trends toward greater reductions in CHD risk were observed in those with lower intakes of saturated fat or trans fat or higher intakes of vegetables/fruits.ConclusionsOver a mean of 8.1 years, a dietary intervention that reduced total fat intake and increased intakes of vegetables, fruits, and grains did not significantly reduce the risk of CHD, stroke, or CVD in postmenopausal women and achieved only modest effects on CVD risk factors, suggesting that more focused diet and lifestyle interventions may be needed to improve risk factors and reduce CVD risk.Clinical Trials RegistrationClinicalTrials.gov Identifier: NCT00000611
TL;DR: This article investigated the degree to which A. Bandura's (1997) hypothesized sources of selfefficacy predict the science self-efficacy beliefs of middle school students and found that only mastery experiences, vicarious experiences, social persuasions, physiological arousal, and self- efficacy significantly predicted science self efficacy.
Abstract: The purpose of this study was to investigate the degree to which A. Bandura's (1997) hypothesized sources of self-efficacy predict the science self-efficacy beliefs of middle school students (N ¼ 319), to replicate previous findings that science self-efficacy predicts science achievement, and to explore how science self-efficacy and its antecedents differ by gender. Significant correlations were found between mastery experiences, vicarious experiences, social persuasions, physiological arousal, and self- efficacy. Only mastery experiences significantly predicted science self-efficacy. Girls reported stronger science self-efficacy than did boys. Findings support and extend the theoretical tenets of Bandura's social cognitive theory. 2006 Wiley Periodicals, Inc. J Res Sci Teach 43: 485-499, 2006 The purpose of this study was to investigate the degree to which Bandura's (1997) hypothesized sources of self-efficacy predict the science self-efficacy beliefs of middle school students. Self-efficacy has been found to be a strong predictor of academic achievement, course selection, and career decisions across domains and age levels. Information about the antecedents of self-efficacy may help science educators facilitate student progress in science during the middle school years and into high school. Although virtually all students take at least 1 year of science in high school, the number who take additional science courses is considerably lower. Only 60% of students take 2 years of high school science and the percentage drops to 25% who take 3 years of science (National Center for Educational Statistics (NCES), 2002). Even fewer students take advanced science courses: 16% take Advanced Placement (AP) biology, 6% AP chemistry, and 4% AP physics. Seeking to increase science course-taking and achievement, science educators have examined a wide range of factors that influence academic choices and performance. One potentially powerful influence is the confidence with which students approach science (Andre,
University at Buffalo1, Medical College of Wisconsin2, Fred Hutchinson Cancer Research Center3, Memorial Hospital of Rhode Island4, Pfizer5, University of Nevada, Reno6, University of Miami7, University of Minnesota8, University of Massachusetts Medical School9, Emory University10, National Institutes of Health11, University of California, Davis12, Yeshiva University13, University of Wisconsin-Madison14, Stanford University15, Northwestern University16, University of Iowa17, Kaiser Permanente18, University of Arizona19, University of Washington20, Rush University Medical Center21, Wake Forest University22, University of Texas at San Antonio23, University of California, Los Angeles24, University of California, San Diego25, University of Cincinnati26, Baylor College of Medicine27, University of North Carolina at Chapel Hill28, Wayne State University29, Howard University30, George Washington University31, University of California, Irvine32, Ohio State University33, University of Tennessee Health Science Center34, University of Pittsburgh35, Stony Brook University36, Rutgers University37, University of Alabama at Birmingham38, University of Florida39, Harvard University40
TL;DR: Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women, and the long latency associated with the development of colorescopy cancer, along with the seven-year duration of the trial, may have contributed to this null finding.
Abstract: Background Higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials. However, randomized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking. Methods We conducted a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women from 40 Women’s Health Initiative centers: 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 twice daily (1000 mg of elemental calcium and 400 IU of vitamin D3) and 18,106 received a matching placebo for an average of 7.0 years. The incidence of pathologically confirmed colorectal cancer was the designated secondary outcome. Baseline levels of serum 25-hydroxyvitamin D were assessed in a nested case–control study. Results The incidence of invasive colorectal cancer did not differ significantly between women assigned to calcium plus vitamin D supplementation and those assigned to placebo (168 and 154 cases; hazard ratio, 1.08; 95 percent confidence interval, 0.86 to 1.34; P = 0.51), and the tumor characteristics were similar in the two groups. The frequency of colorectal-cancer screening and abdominal symptoms was similar in the two groups. There were no significant treatment interactions with baseline characteristics. Conclusions Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women. The long latency associated with the development of colorectal cancer, along with the seven-year duration of the trial, may have contributed to this null finding. Ongoing follow-up will assess the longer-term effect of this intervention. (ClinicalTrials.gov number, NCT00000611.)
TL;DR: Patients in both the surgery and the nonoperative treatment groups improved substantially over a 2-year period, and conclusions about the superiority or equivalence of the treatments are not warranted based on the intent-to-treat analysis.
Abstract: Context
Lumbar diskectomy is the most common surgical procedure performed for back and leg symptoms in US patients, but the efficacy of the procedure relative to nonoperative care remains controversial.
TL;DR: The concept of enterprise agility is defined and deconstruct, the underlying capabilities that support enterprise agility are explored, the enabling role of information technology (IT) and digital options are explained, and a method for measuring enterprise Agility is proposed.
Abstract: In turbulent environments, enterprise agility, that is, the ability of firms to sense environmental change and respond readily, is an important determinant of firm success. We define and deconstruct enterprise agility, delineate enterprise agility from similar concepts in the business research literature, explore the underlying capabilities that support enterprise agility, explicate the enabling role of information technology (IT) and digital options, and propose a method for measuring enterprise agility. The concepts in this paper are offered as foundational building blocks for the overall research program on enterprise agility and the enabling role of IT.
TL;DR: Pregnancy is not “protective” with respect to risk of relapse of major depression, and women with histories of depression who are euthymic in the context of ongoing antidepressant therapy should be aware of the association of depressive relapse during pregnancy with antidepressant discontinuation.
Abstract: ContextPregnancy has historically been described as a time of emotional well-being, providing “protection” against psychiatric disorder. However, systematic delineation of risk of relapse in women who maintain or discontinue pharmacological treatment during pregnancy is necessary.ObjectiveTo describe risk of relapse in pregnant women who discontinued antidepressant medication proximate to conception compared with those who maintained treatment with these medications.Design, Setting, and PatientsA prospective naturalistic investigation using longitudinal psychiatric assessments on a monthly basis across pregnancy; a survival analysis was conducted to determine time to relapse of depression during pregnancy. A total of 201 pregnant women were enrolled between March 1999 and April 2003 from 3 centers with specific expertise in the treatment of psychiatric illness during pregnancy. The cohort of women was recruited from (1) within the hospital clinics, (2) self-referral via advertisements and community outreach detailing the study, and (3) direct referrals from the community. Participants were considered eligible if they (1) had a history of major depression prior to pregnancy, (2) were less than 16 weeks' gestation, (3) were euthymic for at least 3 months prior to their last menstrual period, and (4) were currently or recently (<12 weeks prior to last menstrual period) receiving antidepressant treatment. Of the 201 participants, 13 miscarried, 5 electively terminated their pregnancy, 12 were lost to follow-up prior to completion of pregnancy, and 8 chose to discontinue participation in the study.Main Outcome MeasureRelapse of major depression defined as fulfilling Structured Clinical Interview for DSM-IV [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition] Diagnosis (SCID) criteria.ResultsAmong the 201 women in the sample, 86 (43%) experienced a relapse of major depression during pregnancy. Among the 82 women who maintained their medication throughout their pregnancy, 21 (26%) relapsed compared with 44 (68%) of the 65 women who discontinued medication. Women who discontinued medication relapsed significantly more frequently over the course of their pregnancy compared with women who maintained their medication (hazard ratio, 5.0; 95% confidence interval, 2.8-9.1; P<.001).ConclusionsPregnancy is not “protective” with respect to risk of relapse of major depression. Women with histories of depression who are euthymic in the context of ongoing antidepressant therapy should be aware of the association of depressive relapse during pregnancy with antidepressant discontinuation.
King's College1, Carlos III Health Institute2, University College London3, Georgia Regents University4, King's College London5, University of North Carolina at Chapel Hill6, University of Naples Federico II7, Southern General Hospital8, Tel Aviv University9, Royal College of Nursing10, Baylor College of Medicine11, Emory University12, University of Cambridge13, North Tyneside General Hospital14, St Thomas' Hospital15, Icahn School of Medicine at Mount Sinai16
TL;DR: An international pilot study assessing feasibility, validity, and acceptability of a nonmotor questionnaire (NMSQuest) found NMS were highly significantly more prevalent across all disease stages and the number of symptoms correlated significantly with advancing disease and duration of disease.
Abstract: Nonmotor symptoms (NMS) of Parkinson's disease (PD) are not well recognized in clinical practice, either in primary or in secondary care, and are frequently missed during routine consultations. There is no single instrument (questionnaire or scale) that enables a comprehensive assessment of the range of NMS in PD both for the identification of problems and for the measurement of outcome. Against this background, a multidisciplinary group of experts, including patient group representatives, has developed an NMS screening questionnaire comprising 30 items. This instrument does not provide an overall score of disability and is not a graded or rating instrument. Instead, it is a screening tool designed to draw attention to the presence of NMS and initiate further investigation. In this article, we present the results from an international pilot study assessing feasibility, validity, and acceptability of a nonmotor questionnaire (NMSQuest). Data from 123 PD patients and 96 controls were analyzed. NMS were highly significantly more prevalent in PD compared to controls (PD NMS, median = 9.0, mean = 9.5 vs. control NMS, median = 5.5, mean = 4.0; Mann-Whitney, Kruskal-Wallis, and t test, P < 0.0001), with PD patients reporting at least 10 different NMS on average per patient. In PD, NMS were highly significantly more prevalent across all disease stages and the number of symptoms correlated significantly with advancing disease and duration of disease. Furthermore, frequently, problems such as diplopia, dribbling, apathy, blues, taste and smell problems were never previously disclosed to the health professionals.
Centers for Disease Control and Prevention1, Vanderbilt University2, Connecticut Agricultural Experiment Station3, University of California, Berkeley4, Oregon Department of Human Services5, Johns Hopkins University6, University of Rochester7, Veterans Health Administration8, Emory University9, University of Texas at San Antonio10
TL;DR: The rate of antibiotic-resistant invasive pneumococcal infections decreased in young children and older persons after the introduction of the conjugate vaccine, and there was an increase in infections caused by serotypes not included in the vaccine.
Abstract: BACKGROUND Five of seven serotypes in the pneumococcal conjugate vaccine, introduced for infants in the United States in 2000, are responsible for most penicillin-resistant infections. We examined the effect of this vaccine on invasive disease caused by resistant strains. METHODS We used laboratory-based data from Active Bacterial Core surveillance to measure disease caused by antibiotic-nonsusceptible pneumococci from 1996 through 2004. Cases of invasive disease, defined as disease caused by pneumococci isolated from a normally sterile site, were identified in eight surveillance areas. Isolates underwent serotyping and susceptibility testing. RESULTS Rates of invasive disease caused by penicillin-nonsusceptible strains and strains not susceptible to multiple antibiotics peaked in 1999 and decreased by 2004, from 6.3 to 2.7 cases per 100,000 (a decline of 57 percent; 95 percent confidence interval, 55 to 58 percent) and from 4.1 to 1.7 cases per 100,000 (a decline of 59 percent; 95 percent confidence interval, 58 to 60 percent), respectively. Among children under two years of age, disease caused by penicillin-nonsusceptible strains decreased from 70.3 to 13.1 cases per 100,000 (a decline of 81 percent; 95 percent confidence interval, 80 to 82 percent). Among persons 65 years of age or older, disease caused by penicillin-nonsusceptible strains decreased from 16.4 to 8.4 cases per 100,000 (a decline of 49 percent). Rates of resistant disease caused by vaccine serotypes fell 87 percent. An increase was seen in disease caused by serotype 19A, a serotype not included in the vaccine (from 2.0 to 8.3 per 100,000 among children under two years of age). CONCLUSIONS The rate of antibiotic-resistant invasive pneumococcal infections decreased in young children and older persons after the introduction of the conjugate vaccine. There was an increase in infections caused by serotypes not included in the vaccine.
TL;DR: The potential surface can be discontinuous when there is bond breaking and forming closer than three bonds from the MM region and the behavior of ONIOM with electronic embedding can be more stable than QM/MM with electronicembedding.
Abstract: The purpose of this paper is 2-fold. First, we present several extensions to the ONIOM(QM:MM) scheme. In its original formulation, the electrostatic interaction between the regions is included at the classical level. Here we present the extension to electronic embedding. We show how the behavior of ONIOM with electronic embedding can be more stable than QM/MM with electronic embedding. We also investigate the link atom correction, which is implicit in ONIOM but not in QM/MM. Second, we demonstrate some of the practical aspects of ONIOM(QM:MM) calculations. Specifically, we show that the potential surface can be discontinuous when there is bond breaking and forming closer than three bonds from the MM region.
TL;DR: This review highlights gender-specific issues in ischemic heart disease presentation, evaluation, and outcomes with a special focus on the results derived from the National Institutes of Health-National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation study.
TL;DR: The incidence of sepsis is disproportionately increased in elderly adults, and age is an independent predictor of mortality, which has implications for patient care and health care resource prioritization.
Abstract: Objective:Sepsis is an increasingly common and lethal medical condition that occurs in people of all ages. The influence of age on sepsis risk and outcome is incompletely understood. We sought to determine the independent effect of age on the incidence, severity, and outcome of adult sepsis.Design:L
TL;DR: The current understanding of the process of estrogen deficiency-mediated bone destruction is presented and some recent findings and hypotheses to explain estrogen action in bone are explored.
Abstract: Estrogen plays a fundamental role in skeletal growth and bone homeostasis in both men and women. Although remarkable progress has been made in our understanding of how estrogen deficiency causes bone loss, the mechanisms involved have proven to be complex and multifaceted. Although estrogen is established to have direct effects on bone cells, recent animal studies have identified additional unexpected regulatory effects of estrogen centered at the level of the adaptive immune response. Furthermore, a potential role for reactive oxygen species has now been identified in both humans and animals. One major challenge is the integration of a multitude of redundant pathways and cytokines, each apparently capable of playing a relevant role, into a comprehensive model of postmenopausal osteoporosis. This Review presents our current understanding of the process of estrogen deficiency-mediated bone destruction and explores some recent findings and hypotheses to explain estrogen action in bone. Due to the inherent difficulties associated with human investigation, many of the lessons learned have been in animal models. Consequently, many of these principles await further validation in humans.
TL;DR: This study evaluated nonoutbreak community-acquired S. aureus skin and soft-tissue infections in patients in a large urban setting who were receiving care at a large hospital and its affiliated clinics in urban Atlanta, Georgia.
Abstract: In this study of 384 persons with microbiologically confirmed community-onset Staphylococcus aureus skin and soft-tissue infection, community-acquired methicillin-resistant Staphylococcus aureus (M...
TL;DR: Using a case study method, this paper examines the cultural values and knowledge management approaches within a large global information services company and one of its knowledge communities and highlights the influence of culture on the use of knowledge management technologies and the outcomes of such use.
Abstract: Knowledge management to facilitate the creation, storage, transfer, and application of knowledge in organizations has received wide attention in practice and research in the past several years. Often cited as a significant challenge in knowledge management practices is the issue of organizational culture. Although many studies raise the issue of organizational culture's influence on knowledge management success, few investigate the way in which this influence manifests itself. This paper aims to explore how organizational culture influences knowledge management practices. Using a case study method, we examine the cultural values and knowledge management approaches within a large global information services company and one of its knowledge communities. The findings highlight the influence of culture on the use of knowledge management technologies and the outcomes of such use.
TL;DR: This research is placed in theoretical context by arguing for the critical role of reminiscing in developmental process and outcome.
Abstract: Initial research on maternal reminiscing style established clear and consistent individual differences that vary along a dimension of maternal elaboration and that are related to children's developing autobiographical skills. More recent research has linked maternal elaborative reminiscing to strategic memory development, language and literacy skills, developing attachment relationships, and understanding of self, other, and mind. In this review, this research is placed in theoretical context by arguing for the critical role of reminiscing in developmental process and outcome.
TL;DR: The use of bioconjugated nanoparticles for the delivery and targeting of anticancer drugs and imaging contrast agents is discussed.
Abstract: Nanotechnology refers to the interactions of cellular and molecular components and engineered materials-typically, clusters of atoms, molecules, and molecular fragments into incredibly small particles-between 1 and 100 nm. Nanometer-sized particles have novel optical, electronic, and structural properties that are not available either in individual molecules or bulk solids. The concept of nanoscale devices has led to the development of biodegradable self-assembled nanoparticles, which are being engineered for the targeted delivery of anticancer drugs and imaging contrast agents. Nanoconstructs such as these should serve as customizable, targeted drug delivery vehicles capable of ferrying large doses of chemotherapeutic agents or therapeutic genes into malignant cells while sparing healthy cells. Such "smart" multifunctional nanodevices hold out the possibility of radically changing the practice of oncology, allowing easy detection and then followed by effective targeted therapeutics at the earliest stages of the disease. In this article, we briefly discuss the use of bioconjugated nanoparticles for the delivery and targeting of anticancer drugs.